)| PMID |
17586614 ( ) |
|---|---|
| Title | Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. |
| Abstract | Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue. Medicine, Columbia, Missouri 65212, USA. |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | 115 | angiotensin ii | ang ii | ANG | |
| 6081 | INS | insulin | 103 | INS | insulin | |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | 45 | IGF-1 | |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | 28 | Akt | PKB | |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | 18 | nadph oxidase | |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 15 | p110 | phosphatidylinositol 3 kinase | PI3K | PI3-K | |
| 9958 | REN | renin | 15 | renin | |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | 14 | eNOS | |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | 13 | TNF-alpha | tnf alpha | |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | 12 | p40 | p38 | MAPK | MAP | |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | 11 | MLC | |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 9 | SOD | superoxide dismutase | |
| 2367 | CRP | C-reactive protein, pentraxin-related | 7 | CRP | c reactive protein | |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | 7 | Rac1 | |
| 670 | RHOD | ras homolog gene family, member D | 7 | Rho | |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | 5 | mcp 1 | MCP-1 | |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | 5 | GLUT4 | glucose transporter 4 | |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | 5 | p47 | |
| 3327 | ELN | elastin (supravalvular aortic stenosis, Williams-Beuren syndrome) | 4 | elastin | |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | 4 | Bcl-2 | bcl 2 | |
| 1516 | CAT | catalase | 4 | catalase | |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | 4 | IL-6 | il 6 | |
| 6125 | IRS1 | insulin receptor substrate 1 | 4 | IRS-1 | |
| 6091 | INSR | insulin receptor | 3 | insulin receptor | |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | 3 | Nox2 | NOX2 | |
| 6881 | MAPK8 | mitogen-activated protein kinase 8 | 3 | JNK | |
| 11362 | STAT1 | signal transducer and activator of transcription 1, 91kDa | 3 | STAT | |
| 8816 | PDPK1 | 3-phosphoinositide dependent protein kinase-1 | 3 | 3 phosphoinositide dependent protein kinase 1 | PDK-1 | |
| 4910 | HIF1A | hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) | 3 | hif 1 | HIF-1 | hypoxia inducible factor 1 | |
| 29826 | MYLK3 | myosin light chain kinase 3 | 3 | mlc kinase | |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | 3 | p22 | |
| 17937 | CUZD1 | CUB and zona pellucida-like domains 1 | 2 | erg 1 | Erg-1 | |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | 2 | p67 | |
| 1509 | CASP8 | caspase 8, apoptosis-related cysteine peptidase | 2 | caspase 8 | caspase-8 | |
| 1876 | CFLAR | CASP8 and FADD-like apoptosis regulator | 2 | c-FLIP | c flip | |
| 10840 | SHC1 | SHC (Src homology 2 domain containing) transforming protein 1 | 2 | Shc | |
| 3796 | FOS | v-fos FBJ murine osteosarcoma viral oncogene homolog | 2 | ap 1 | AP-1 | |
| 5992 | IL1B | interleukin 1, beta | 2 | IL-1 | il 1 | |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | 2 | NF-kappaB | |
| 667 | RHOA | ras homolog gene family, member A | 2 | RhoA | |
| 4566 | GRB2 | growth factor receptor-bound protein 2 | 2 | Grb-2 | |
| 11283 | SRC | v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) | 2 | Src | |
| 9588 | PTEN | phosphatase and tensin homolog (mutated in multiple advanced cancers 1) | 1 | PTEN | |
| 4617 | GSK3B | glycogen synthase kinase 3 beta | 1 | glycogen synthase kinase 3 beta | |
| 8979 | PIK3R1 | phosphoinositide-3-kinase, regulatory subunit 1 (alpha) | 1 | p85 | |
| 7590 | MYLK | myosin light chain kinase | 1 | MLCK | |
| 992 | BCL2L1 | BCL2-like 1 | 1 | bcl xl | |
| 6953 | CD46 | CD46 molecule, complement regulatory protein | 1 | MCP | |
| 3238 | EGR1 | early growth response 1 | 1 | early growth response 1 | |
| 3819 | FOXO1 | forkhead box O1 | 1 | FOXO-1 | |
| 4390 | GNAQ | guanine nucleotide binding protein (G protein), q polypeptide | 1 | g alpha q | |
| 2422 | CS | citrate synthase | 1 | citrate synthase | |
| 6080 | INPPL1 | inositol polyphosphate phosphatase-like 1 | 1 | SHIP-2 | |
| 2362 | CRK | v-crk sarcoma virus CT10 oncogene homolog (avian) | 1 | Crk | |
| 7979 | NR3C2 | nuclear receptor subfamily 3, group C, member 2 | 1 | mineralocorticoid receptor | |
| 29869 | SHC2 | SHC (Src homology 2 domain containing) transforming protein 2 | 1 | Sck | |
| 2707 | ACE | angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 | 1 | angiotensin converting enzyme | |
| 2197 | COL1A1 | collagen, type I, alpha 1 | 1 | collagen | |
| 7978 | NR3C1 | nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) | 1 | glucocorticoid receptor | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 6081 | INS | insulin | INS | 1.0 | A vascular effects of insulin (INS)/IGF-1 INS IGF-1 and counteregulatory effects of angiotensin II (ANG ANG II |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | A vascular effects of insulin (INS)/IGF-1 INS IGF-1 and counteregulatory effects of angiotensin II (ANG ANG II type |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | (INS)/IGF-1 INS IGF-1 and counteregulatory effects of angiotensin II (ANG ANG II type 1 receptor (AT AT 1 R and mineralocorticoid |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | through phosphorylation and secondary activation of endothelial NO synthase (eNOS) eNOS |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | availability of NO via the induction of insulin resistance diminishing eNOS mRNA stability and promoting NADPH oxidase-induced ROS production |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Akt PKB GRE glucocorticoid response element G q G alpha q |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | PKB | 0.8 | Akt PKB GRE glucocorticoid response element G q G alpha q subunit |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | NOX2 | 1.0 | G q G alpha q subunit IRS insulin receptor substrate NOX2 catalytic subunit of NADPH oxidase p22 p47 p40 and p67 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 1.3 | insulin receptor substrate NOX2 catalytic subunit of NADPH oxidase p22 p47 p40 and p67 subunits of NADPH oxidase PH pleckstrin homology |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | p40 | 2.4 | receptor substrate NOX2 catalytic subunit of NADPH oxidase p22 p47 p40 and p67 subunits of NADPH oxidase PH pleckstrin homology domain |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | NOX2 catalytic subunit of NADPH oxidase p22 p47 p40 and p67 subunits of NADPH oxidase PH pleckstrin homology domain PI3-K phosphatidylinositol |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3-K | 2.3 | and p67 subunits of NADPH oxidase PH pleckstrin homology domain PI3-K phosphatidylinositol 3-kinase PIP phosphatidylinositol phosphate PIP2 phosphatidylinositol bisphosphate PIP3 phosphatidylinositol |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | phosphatidylinositol bisphosphate PIP3 phosphatidylinositol ( 3 4 5 -trisphosphate ROK Rho kinase SOD superoxide dismutase |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | PIP3 phosphatidylinositol ( 3 4 5 -trisphosphate ROK Rho kinase SOD superoxide dismutase |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.3 | IRS insulin receptor substrate NOX2 catalytic subunit of NADPH oxidase p22 p47 p40 and p67 subunits of NADPH oxidase PH pleckstrin |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | B opposing effects of ANG II and aldosterone (Aldo) Aldo versus insulin/IGF-1 insulin IGF-1 on |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | of ANG II and aldosterone (Aldo) Aldo versus insulin/IGF-1 insulin IGF-1 on vascular smooth muscle cells (VSMCs) VSMCs |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 cause VSMC relaxation whereas ANG II and mineralocorticoids cause contraction |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Insulin and IGF-1 cause VSMC relaxation whereas ANG II and mineralocorticoids cause contraction |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | MBS myosin-bound serine MLC myosin light chain MLCK MLC kinase Na/Ca Na Ca exch |
| 7590 | MYLK | myosin light chain kinase | MLCK | 2.5 | MBS myosin-bound serine MLC myosin light chain MLCK MLC kinase Na/Ca Na Ca exch Na /Ca Ca exchanger |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | MBS myosin-bound serine MLC myosin light chain MLCK MLC kinase Na/Ca Na Ca exch Na /Ca Ca exchanger |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Functional and metabolic effects of insulin and IGF-1 in the heart |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 modulate glucose transport glycogen synthesis lipid metabolism growth contractility and |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAP | 2.4 | Upon activation of the mitogen-activated protein (MAP) MAP kinase pathway insulin/IGF-1 insulin IGF-1 and ANG II/aldosterone II aldosterone |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | of the mitogen-activated protein (MAP) MAP kinase pathway insulin/IGF-1 insulin IGF-1 and ANG II/aldosterone II aldosterone signaling may converge to cause |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | mitogen-activated protein (MAP) MAP kinase pathway insulin/IGF-1 insulin IGF-1 and ANG II/aldosterone II aldosterone signaling may converge to cause deleterious effects |
| 3796 | FOS | v-fos FBJ murine osteosarcoma viral oncogene homolog | AP-1 | 1.3 | AP-1 activating protein-1 Crk protein exhibiting the Src homology 2 (SH2) |
| 2362 | CRK | v-crk sarcoma virus CT10 oncogene homolog (avian) | Crk | 0.3 | AP-1 activating protein-1 Crk protein exhibiting the Src homology 2 (SH2) SH2 domain Erg-1 |
| 11283 | SRC | v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) | Src | 0.3 | AP-1 activating protein-1 Crk protein exhibiting the Src homology 2 (SH2) SH2 domain Erg-1 early growth response-1 gene |
| 17937 | CUZD1 | CUB and zona pellucida-like domains 1 | Erg-1 | 1.0 | Crk protein exhibiting the Src homology 2 (SH2) SH2 domain Erg-1 early growth response-1 gene HIF-1 hypoxia-inducible factor-1 Sch phosphotyrosine adaptor |
| 4910 | HIF1A | hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) | HIF-1 | 0.9 | homology 2 (SH2) SH2 domain Erg-1 early growth response-1 gene HIF-1 hypoxia-inducible factor-1 Sch phosphotyrosine adaptor molecule Sck adaptor protein GLUT4 |
| 29869 | SHC2 | SHC (Src homology 2 domain containing) transforming protein 2 | Sck | 0.9 | growth response-1 gene HIF-1 hypoxia-inducible factor-1 Sch phosphotyrosine adaptor molecule Sck adaptor protein GLUT4 glucose transporter 4 |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | GLUT4 | 1.6 | HIF-1 hypoxia-inducible factor-1 Sch phosphotyrosine adaptor molecule Sck adaptor protein GLUT4 glucose transporter 4 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II and aldosterone/corticosterone aldosterone corticosterone antagonism to metabolic actions of |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | aldosterone/corticosterone aldosterone corticosterone antagonism to metabolic actions of insulin/IGF-1 insulin IGF-1 in skeletal muscle |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | of key tyrosine residues in IRS and reduced activation of Akt |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | overexpresses the renin gene with subsequent elevated tissue levels of ANG II relative to Sprague-Dawley (SD) SD control |
| 3327 | ELN | elastin (supravalvular aortic stenosis, Williams-Beuren syndrome) | elastin | 1.0 | The green autofluorescence is specific for elastin fibers |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | as seen in cardiometabolic syndrome contribute to altered insulin/IGF-1 insulin IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Both insulin and IGF-1 receptors exist in CV tissue ( 186 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Activation of the insulin receptor (IR) IR and IGF-1 receptor ligand-activated transmembrane receptors with tyrosine kinase activity phosphorylates intracellular |
| 10840 | SHC1 | SHC (Src homology 2 domain containing) transforming protein 1 | Shc | 0.9 | intracellular substrates including IR substrate (IRS) IRS family members and Shc which in turn serve as docking proteins for downstream signaling |
| 11283 | SRC | v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) | Src | 0.3 | IRS phosphorylation of tyrosine moieties results in the engagement of Src homology 2 (SH2) SH2 domain-binding motifs for SH2 domain signaling |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | motifs for SH2 domain signaling molecules including phosphatidyl 3-kinase (PI3K) PI3K and Grb-2 |
| 4566 | GRB2 | growth factor receptor-bound protein 2 | Grb-2 | 0.6 | SH2 domain signaling molecules including phosphatidyl 3-kinase (PI3K) PI3K and Grb-2 |
| 8979 | PIK3R1 | phosphoinositide-3-kinase, regulatory subunit 1 (alpha) | p85 | 0.6 | When SH2 domains of the p85 regulatory subunit bind to tyrosine-phosphorylated motifs on IRS-1 this activates |
| 6125 | IRS1 | insulin receptor substrate 1 | IRS-1 | 1.2 | of the p85 regulatory subunit bind to tyrosine-phosphorylated motifs on IRS-1 this activates the preassociated p110 catalytic subunit to generate phosphatidylinositol |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | p110 | 1.3 | bind to tyrosine-phosphorylated motifs on IRS-1 this activates the preassociated p110 catalytic subunit to generate phosphatidylinositol 3 4 5-trisphosphate [PI( PI |
| 8816 | PDPK1 | 3-phosphoinositide dependent protein kinase-1 | PDK-1 | 0.6 | to the pleckstrin homology domain in 3-phosphoinositide-dependent protein kinase-1 (PDK-1), PDK-1 resulting in its phosphorylation and the activation of other downstream |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | PKB | 0.8 | phosphorylation and the activation of other downstream serine-threonine kinases including PKB (Akt) Akt and atypical PKC isoforms which mediate a number |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | the activation of other downstream serine-threonine kinases including PKB (Akt) Akt and atypical PKC isoforms which mediate a number of metabolic |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | GLUT4 | 1.6 | a number of metabolic actions including glucose transporter 4 (GLUT4) GLUT4 translocation to the membrane leading to glucose uptake in myocardial |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Growth and remodeling responses to insulin and IGF-1 generally involves both STAT and MAPK signaling pathways |
| 11362 | STAT1 | signal transducer and activator of transcription 1, 91kDa | STAT | 0.3 | and remodeling responses to insulin and IGF-1 generally involves both STAT and MAPK signaling pathways |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | responses to insulin and IGF-1 generally involves both STAT and MAPK signaling pathways |
| 6125 | IRS1 | insulin receptor substrate 1 | IRS-1 | 1.2 | This involves tyrosine-phosphorylated IRS-1 or Shc binding to the SH2 domain of Grb-2 which |
| 10840 | SHC1 | SHC (Src homology 2 domain containing) transforming protein 1 | Shc | 0.9 | This involves tyrosine-phosphorylated IRS-1 or Shc binding to the SH2 domain of Grb-2 which results in |
| 4566 | GRB2 | growth factor receptor-bound protein 2 | Grb-2 | 0.6 | tyrosine-phosphorylated IRS-1 or Shc binding to the SH2 domain of Grb-2 which results in the activation of the preassociated GTP exchange |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | the GTP-binding protein Ras which phosphorylates/activates phosphorylates activates MEK and MAPK |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | talk from signaling pathways of heterologous receptors such as the ANG II type 1 (AT AT 1 receptor (AT AT 1 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Protein tyrosine phosphatases which dephosphorylate IR and the IGF-1 receptor as well as lipid phosphatases (i.e., i.e. SHIP-2 and |
| 6080 | INPPL1 | inositol polyphosphate phosphatase-like 1 | SHIP-2 | 0.3 | the IGF-1 receptor as well as lipid phosphatases (i.e., i.e. SHIP-2 and PTEN which dephosphorylate PI( PI 3 4 5 P |
| 9588 | PTEN | phosphatase and tensin homolog (mutated in multiple advanced cancers 1) | PTEN | 0.3 | receptor as well as lipid phosphatases (i.e., i.e. SHIP-2 and PTEN which dephosphorylate PI( PI 3 4 5 P 3 are |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | 3 are involved in the negative regulation of insulin and IGF-1 signaling pathways ( 220 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Inappropriate activation of these phosphatases may contribute to insulin/IGF-1 insulin IGF-1 resistance in CV tissue as well as liver skeletal muscle |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Vascular Actions of Insulin/IGF-1 Insulin IGF-1 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Vascular relaxation effects of insulin/IGF-1 insulin IGF-1 are mediated in part by endothelial cell production of NO |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | IR/IGF-1 IR IGF-1 receptor mediation of PI3K/PDK-1/Akt PI3K PDK-1 Akt phosphorylation/activation phosphorylation activation |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | IR/IGF-1 IR IGF-1 receptor mediation of PI3K/PDK-1/Akt PI3K PDK-1 Akt phosphorylation/activation phosphorylation activation leads to stimulation of endothelial |
| 8816 | PDPK1 | 3-phosphoinositide dependent protein kinase-1 | PDK-1 | 0.6 | IR/IGF-1 IR IGF-1 receptor mediation of PI3K/PDK-1/Akt PI3K PDK-1 Akt phosphorylation/activation phosphorylation activation leads to stimulation of endothelial NO |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | IR/IGF-1 IR IGF-1 receptor mediation of PI3K/PDK-1/Akt PI3K PDK-1 Akt phosphorylation/activation phosphorylation activation leads to stimulation of endothelial NO synthase |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | phosphorylation activation leads to stimulation of endothelial NO synthase (eNOS) eNOS enzyme activity to produce NO |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Phosphorylated/activated Phosphorylated activated Akt in turn phosphorylates human eNOS at Ser resulting in enhanced |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | Phosphorylated/activated Phosphorylated activated Akt in turn phosphorylates human eNOS at Ser resulting in enhanced eNOS activity ( 236 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | in turn phosphorylates human eNOS at Ser resulting in enhanced eNOS activity ( 236 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 also increase vascular smooth muscle cell (VSMC) VSMC production of |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Thus insulin and IGF-1 promote vascular relaxation in part via increases in NO bioavailability |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Insulin also promotes vascular relaxation by attenuating agonist (i.e., i.e. ANG II -induced increases in cytosolic calcium Ca and myosin light |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | increases in cytosolic calcium Ca and myosin light chain (MLC) MLC kinase activity ( 13 174 191 |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | By enhancing MLC phosphatase activity insulin and IGF-1 reduce MLC kinase activity and |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | By enhancing MLC phosphatase activity insulin and IGF-1 reduce MLC kinase activity and thus Ca -sensitive contraction ( |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | By enhancing MLC phosphatase activity insulin and IGF-1 reduce MLC kinase activity and thus Ca -sensitive contraction ( 13 125 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II Actions on the Vasculature |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | There is accumulating evidence that ANG II in addition to its vasoconstriction effects attenuates the CVand |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | attenuates the CVand skeletal muscle metabolic actions of insulin and IGF-1 ( 115 186 190 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | The mechanisms involved in these inhibitory effects of ANG II include the generation of ROS and the activation of |
| 667 | RHOA | ras homolog gene family, member A | RhoA | 0.9 | of ROS and the activation of small-molecular-weight proteins such as RhoA and Rac1 ( 9 66 189 190 ( Figs 1 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | and the activation of small-molecular-weight proteins such as RhoA and Rac1 ( 9 66 189 190 ( Figs 1 and 2 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Indeed there is increasing evidence indicating that ANG II contributes to insulin resistance and other components of CMS |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II exerts inflammatory effects and promotes vascular growth/remodeling, growth remodeling |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | ROS activate transcription factors such as TNF-alpha monocyte chemoattractant protein (MCP)-1, MCP -1 IL-6 and C-reactive protein |
| 6953 | CD46 | CD46 molecule, complement regulatory protein | MCP | 0.6 | activate transcription factors such as TNF-alpha monocyte chemoattractant protein (MCP)-1, MCP -1 IL-6 and C-reactive protein (CRP) CRP |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | IL-6 | 1.3 | factors such as TNF-alpha monocyte chemoattractant protein (MCP)-1, MCP -1 IL-6 and C-reactive protein (CRP) CRP |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | chemoattractant protein (MCP)-1, MCP -1 IL-6 and C-reactive protein (CRP) CRP |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | TNF-alpha in turn impedes insulin- and IGF-1-mediated eNOS activation as well |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | TNF-alpha in turn impedes insulin- and IGF-1-mediated eNOS activation as well as the antiapoptotic actions of insulin and |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | activation as well as the antiapoptotic actions of insulin and IGF-1 ( 128 186 190 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Animal Model to Investigate the Role of ANG II in Mediating Insulin/IGF-1 Insulin IGF-1 Resistance |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Investigate the Role of ANG II in Mediating Insulin/IGF-1 Insulin IGF-1 Resistance |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | displays an activated tissue renin-angiotensin-aldosterone system (RAAS) RAAS with increased ANG II levels and increased plasma mineralocorticoids to evaluate the role |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | increased plasma mineralocorticoids to evaluate the role of increased tissue ANG II and mineralocorticoids in mediating CVD as well as skeletal |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | ( Fig 4 lipid peroxidation inflammation (increased increased expression of TNF-alpha and CRP and indexes of apoptosis compared with Sprague-Dawley rats |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | 4 lipid peroxidation inflammation (increased increased expression of TNF-alpha and CRP and indexes of apoptosis compared with Sprague-Dawley rats |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | vasculature there was a marked reduction in insulin stimulation of Akt signaling eNOS Ser phosphorylation/activation phosphorylation activation |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | was a marked reduction in insulin stimulation of Akt signaling eNOS Ser phosphorylation/activation phosphorylation activation |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | an AT 1 R blocker or the superoxide dismutase (SOD)/catalase SOD catalase minetic tempol |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | data have suggested that vascular RAAS activation and insulin/IGF-1 insulin IGF-1 resistance perpetuate each other and concordantly contribute to endothelial dysfunction |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Insulin and ANG II in the Heart |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 exert a number of metabolic and functional effects on the |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | GLUT4 | 1.6 | skeletal muscle glucose uptake in cardiomyocytes involves mobilization of insulin-responsive GLUT4 via a PI3K/Akt PI3K Akt signaling pathway ( 2 98 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | in cardiomyocytes involves mobilization of insulin-responsive GLUT4 via a PI3K/Akt PI3K Akt signaling pathway ( 2 98 ( Fig 2 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | cardiomyocytes involves mobilization of insulin-responsive GLUT4 via a PI3K/Akt PI3K Akt signaling pathway ( 2 98 ( Fig 2 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | Furthermore in cardiomyocytes insulin stimulation of the PI3K/Akt PI3K Akt pathway results in the phosphorylation and nuclear exclusion of |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Furthermore in cardiomyocytes insulin stimulation of the PI3K/Akt PI3K Akt pathway results in the phosphorylation and nuclear exclusion of the |
| 3819 | FOXO1 | forkhead box O1 | FOXO-1 | 0.3 | the phosphorylation and nuclear exclusion of the forkhead transcription factor FOXO-1 which further modulates glucose and lipid metabolism ( 125 137 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 normally enhance cardiac contractility ( 22 153 163 -165 186 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | 153 163 -165 186 190 via signaling through the PI3K/Akt PI3K Akt pathway |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | 163 -165 186 190 via signaling through the PI3K/Akt PI3K Akt pathway |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 also enhance cardiomyocyte myofilament Ca sensitivity ( 42 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | Increases in myocardial NO production through the PI3K/Akt/eNOS PI3K Akt eNOS pathway also appear to contribute to the inotropic |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Increases in myocardial NO production through the PI3K/Akt/eNOS PI3K Akt eNOS pathway also appear to contribute to the inotropic effects |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | Increases in myocardial NO production through the PI3K/Akt/eNOS PI3K Akt eNOS pathway also appear to contribute to the inotropic effects of |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | determinant of myocardial blood flow (MBF), MBF and insulin and IGF-1 enhance MBF and promote capillary recruitment in the heart ( |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | between the metabolic and coronary vascular actions of insulin and IGF-1 in the heart with increases in capillary recruitment and MBF-enhancing |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | These actions of insulin and IGF-1 as well as their direct effects on cardiomyocytes also enhance |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 also regulate developmental and physiological growth and remodeling of the |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | The peptides accomplish these effects by signaling through the PI3K/Akt PI3K Akt pathway ( 78 102 223 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | peptides accomplish these effects by signaling through the PI3K/Akt PI3K Akt pathway ( 78 102 223 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Downstream from Akt activation of the mammalian target of rapamycin promotes cardiac growth |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Signaling through the Akt pathway also exerts antiapoptotic effects on the myocardium ( 163 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Indeed one apoptotic signaling system modulated by the Akt pathway involves the phosphorylation and nuclear exclusion of the FOXO |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin and IGF-1 also promote survival by direct phosphorylation/inactivation phosphorylation inactivation of Bad |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl-2 | 1.0 | direct phosphorylation/inactivation phosphorylation inactivation of Bad a member of the Bcl-2 family which promotes apoptosis by binding to and antagonizing the |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | Bcl-2 | 1.0 | the action of prosurvival members of the family such as Bcl-2 and Bcl-XL |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Insulin/IGF-1 Insulin IGF-1 activation of Akt may also interfere with stress-activated protein kinases |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Insulin/IGF-1 Insulin IGF-1 activation of Akt may also interfere with stress-activated protein kinases such as JNK |
| 6881 | MAPK8 | mitogen-activated protein kinase 8 | JNK | 0.9 | Akt may also interfere with stress-activated protein kinases such as JNK p38 and MAPK pathways critically involved in the induction of |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | p38 | 2.4 | may also interfere with stress-activated protein kinases such as JNK p38 and MAPK pathways critically involved in the induction of apoptosis |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | interfere with stress-activated protein kinases such as JNK p38 and MAPK pathways critically involved in the induction of apoptosis following exposure |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Finally Akt activation increases the expression of c-FLIP a caspase-8 homologene that |
| 1876 | CFLAR | CASP8 and FADD-like apoptosis regulator | c-FLIP | 2.5 | Finally Akt activation increases the expression of c-FLIP a caspase-8 homologene that inhibits TNF receptor family-induced apoptosis ( |
| 1509 | CASP8 | caspase 8, apoptosis-related cysteine peptidase | caspase-8 | 2.0 | Finally Akt activation increases the expression of c-FLIP a caspase-8 homologene that inhibits TNF receptor family-induced apoptosis ( 142 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF | 0.8 | increases the expression of c-FLIP a caspase-8 homologene that inhibits TNF receptor family-induced apoptosis ( 142 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | pathological cardiomyocyte hypertrophy is promoted by interactions of insulin/IGF-1 insulin IGF-1 with growth factors such as ANG II catecholamines endothelin and |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | interactions of insulin/IGF-1 insulin IGF-1 with growth factors such as ANG II catecholamines endothelin and mineralocorticoids to stimulate signaling pathways involving |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | II catecholamines endothelin and mineralocorticoids to stimulate signaling pathways involving MAPK p38 MAPK JAK/STAT, JAK STAT and the small-molecular-weight G proteins |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | p38 | 2.4 | catecholamines endothelin and mineralocorticoids to stimulate signaling pathways involving MAPK p38 MAPK JAK/STAT, JAK STAT and the small-molecular-weight G proteins Rho |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | endothelin and mineralocorticoids to stimulate signaling pathways involving MAPK p38 MAPK JAK/STAT, JAK STAT and the small-molecular-weight G proteins Rho and |
| 11362 | STAT1 | signal transducer and activator of transcription 1, 91kDa | STAT | 0.3 | to stimulate signaling pathways involving MAPK p38 MAPK JAK/STAT, JAK STAT and the small-molecular-weight G proteins Rho and Ras ( 163 |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | p38 MAPK JAK/STAT, JAK STAT and the small-molecular-weight G proteins Rho and Ras ( 163 180 186 188 190 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | a seminal feature of insulin resistance is impairment in PI3K/Akt PI3K Akt signaling metabolic pathways whereas other insulin signaling growth pathways |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | seminal feature of insulin resistance is impairment in PI3K/Akt PI3K Akt signaling metabolic pathways whereas other insulin signaling growth pathways including |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | pathways whereas other insulin signaling growth pathways including RAS/MAPK/JAK/STAT RAS MAPK JAK STAT signaling are not inhibited ( 36 89 150 |
| 11362 | STAT1 | signal transducer and activator of transcription 1, 91kDa | STAT | 0.3 | other insulin signaling growth pathways including RAS/MAPK/JAK/STAT RAS MAPK JAK STAT signaling are not inhibited ( 36 89 150 186 190 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | and oxidative stress ( 83 as well as impaired insulin-stimulated eNOS activity and NO production ( 47 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | cellular tetrohydrobiopterin levels and promote the generation of superoxide by eNOS |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | exert antioxidant and anti-inflammatory effects via signaling through the PI3K/Akt PI3K Akt metabolic pathway ( 186 190 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | antioxidant and anti-inflammatory effects via signaling through the PI3K/Akt PI3K Akt metabolic pathway ( 186 190 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II and mineralocorticoids in contrast cause vasoconstriction and enhance the |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Furthermore ANG II and aldosterone interfere with many of the metabolic signaling |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | with many of the metabolic signaling actions of insulin and IGF-1 in the CV system ( 9 80 85 86 102 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II acting through the AT 1 R increases the generation |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Infusion of ANG II impairs endothelium-dependent vasorelaxation ( 31 and this impairment is |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | ( 31 and this impairment is corrected by coadministration of SOD ( 105 indicating the critical role of ROS in ANG |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | SOD ( 105 indicating the critical role of ROS in ANG II-mediated endothelial dysfunction ( 189 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II-stimulated ROS inhibit insulin/IGF-1 insulin IGF-1 signaling through the PI3K/Akt |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | ANG II-stimulated ROS inhibit insulin/IGF-1 insulin IGF-1 signaling through the PI3K/Akt PI3K Akt signaling pathway to activate |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | II-stimulated ROS inhibit insulin/IGF-1 insulin IGF-1 signaling through the PI3K/Akt PI3K Akt signaling pathway to activate eNOS ( 13 125 199 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | ROS inhibit insulin/IGF-1 insulin IGF-1 signaling through the PI3K/Akt PI3K Akt signaling pathway to activate eNOS ( 13 125 199 224 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | signaling through the PI3K/Akt PI3K Akt signaling pathway to activate eNOS ( 13 125 199 224 235 236 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Furthermore ROS generated by ANG II inactivate NO ( 20 120 152 203 and the |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | This creates a cycle of impaired endothelium-derived vasodilation and increased ANG II-mediated vasoconstriction |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II also stimulates RhoA/Rho RhoA Rho kinase activation which decreases |
| 667 | RHOA | ras homolog gene family, member A | RhoA | 0.9 | ANG II also stimulates RhoA/Rho RhoA Rho kinase activation which decreases eNOS expression in part by |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | ANG II also stimulates RhoA/Rho RhoA Rho kinase activation which decreases eNOS expression in part by decreasing |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | II also stimulates RhoA/Rho RhoA Rho kinase activation which decreases eNOS expression in part by decreasing eNOS mRNA stability ( 122 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | kinase activation which decreases eNOS expression in part by decreasing eNOS mRNA stability ( 122 200 ( Fig 1 A |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II acting via its AT 1 R increases VSMC contraction |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | R increases VSMC contraction by increasing intracellular Ca and Ca -MLC sensitization ( 129 233 ( Fig 1 B |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Both processes are mediated in part by ANG II-stimulated generation of ROS in endothelial cells and VSMCs ( |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II also increases Ca -MLC sensitization by stimulating Rho kinase |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | ANG II also increases Ca -MLC sensitization by stimulating Rho kinase activity in VSMCs whereas insulin |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | ANG II also increases Ca -MLC sensitization by stimulating Rho kinase activity in VSMCs whereas insulin and IGF-1 induce relaxation |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | by stimulating Rho kinase activity in VSMCs whereas insulin and IGF-1 induce relaxation by increasing endothelial cell production of NO and |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | increasing endothelial cell production of NO and by reducing Ca -MLC sensitization ( 175 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II decreases the ability of insulin and IGF-1 to decrease |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | ANG II decreases the ability of insulin and IGF-1 to decrease Ca -MLC sensitization by activating Rho kinase which |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | decreases the ability of insulin and IGF-1 to decrease Ca -MLC sensitization by activating Rho kinase which phosphorylates myosin binding protein |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | insulin and IGF-1 to decrease Ca -MLC sensitization by activating Rho kinase which phosphorylates myosin binding protein and thereby inhibits the |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | thereby inhibits the ability of these peptides to dephosphorylate Ca -MLC which leads to increased Ca -MLC phosphorylation ( 186 190 |
| 29823 | MYL6B | myosin, light chain 6B, alkali, smooth muscle and non-muscle | MLC | 1.5 | peptides to dephosphorylate Ca -MLC which leads to increased Ca -MLC phosphorylation ( 186 190 ( Fig 1 B |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | concept is bourne out by the observation that increases in Rho kinas and a decrease in myosin binding protein activity occurs |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | and a decrease in myosin binding protein activity occurs in ANG II-mediated ( 30 and insulin-resistant ( 176 hypertensive rodents |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kappaB | 0.3 | Increased ROS also activate multiple redox signaling pathways including NF-kappaB ( 127 |
| 7794 | NFKB1 | nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) | NF-kappaB | 0.3 | NF-kappaB in turn enhances other ANG II-mediated inflammatory responses by upregulating |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | NF-kappaB in turn enhances other ANG II-mediated inflammatory responses by upregulating other inflammatory molecules such as |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | II-mediated inflammatory responses by upregulating other inflammatory molecules such as TNF-alpha MCP-1 and CRP ( 72 124 |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | MCP-1 | 1.0 | inflammatory responses by upregulating other inflammatory molecules such as TNF-alpha MCP-1 and CRP ( 72 124 |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | by upregulating other inflammatory molecules such as TNF-alpha MCP-1 and CRP ( 72 124 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | TNF-alpha activates several serine kinases including JNK I kappaK-beta and IL-1 |
| 6881 | MAPK8 | mitogen-activated protein kinase 8 | JNK | 0.9 | TNF-alpha activates several serine kinases including JNK I kappaK-beta and IL-1 beta receptor-associated kinase ( 91 which |
| 5992 | IL1B | interleukin 1, beta | IL-1 | 1.0 | TNF-alpha activates several serine kinases including JNK I kappaK-beta and IL-1 beta receptor-associated kinase ( 91 which directly or indirectly increase |
| 6125 | IRS1 | insulin receptor substrate 1 | IRS-1 | 1.2 | 91 which directly or indirectly increase serine phosphorylation of IRS-1/2, IRS-1 2 leading to decreased PI3K/Akt PI3K Akt signaling responses and |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | serine phosphorylation of IRS-1/2, IRS-1 2 leading to decreased PI3K/Akt PI3K Akt signaling responses and subsequent impaired insulin/IGF-1 insulin IGF-1 stimulation |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | phosphorylation of IRS-1/2, IRS-1 2 leading to decreased PI3K/Akt PI3K Akt signaling responses and subsequent impaired insulin/IGF-1 insulin IGF-1 stimulation of |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | PI3K/Akt PI3K Akt signaling responses and subsequent impaired insulin/IGF-1 insulin IGF-1 stimulation of eNOS production of NO and vasodilatation ( 6 |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.9 | signaling responses and subsequent impaired insulin/IGF-1 insulin IGF-1 stimulation of eNOS production of NO and vasodilatation ( 6 51 95 96 |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-alpha | 0.5 | TNF-alpha increases the expression of other inflammatory substance including IL-6 and |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | IL-6 | 1.3 | TNF-alpha increases the expression of other inflammatory substance including IL-6 and CRP |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | increases the expression of other inflammatory substance including IL-6 and CRP |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | CRP in turn appears to attenuate insulin-stimulated NO production in endothelial |
| 6125 | IRS1 | insulin receptor substrate 1 | IRS-1 | 1.2 | insulin-stimulated NO production in endothelial cells by increasing phosphorylation of IRS-1 at Ser and indirectly by enhancing Rho kinase and JNK |
| 670 | RHOD | ras homolog gene family, member D | Rho | 1.4 | increasing phosphorylation of IRS-1 at Ser and indirectly by enhancing Rho kinase and JNK signaling ( 6 217 |
| 6881 | MAPK8 | mitogen-activated protein kinase 8 | JNK | 0.9 | IRS-1 at Ser and indirectly by enhancing Rho kinase and JNK signaling ( 6 217 |
| 2367 | CRP | C-reactive protein, pentraxin-related | CRP | 0.6 | CRP also upregulates VSMC AT 1 Rs ( 225 and increases |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | MCP-1 | 1.0 | 225 and increases the expression of VCAM ICAM E-selectin and MCP-1 in endothelial cells ( 144 thus counterbalancing the antiatherosclerotic and |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | In addition to stimulating membrane NADPH oxidase in vascular cells ANG II in conjunction with other cellular stresses may increase endoplasmic |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | be accentuated by Cu/Zn-SOD Cu Zn-SOD deficiency in response to ANG II ( 43 45 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | in Cu/Zn-SOD, Cu Zn-SOD the most abundant of the three SOD isoforms is associated with increases in ROS and vascular dysfunction |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | As previously noted insulin and IGF-1 generally exert beneficial effects on myocardial mechanical-electrical coupling and both |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | Many of these beneficial effects of insulin and IGF-1 are mediated largely by PI3K/Akt PI3K Akt signaling ( 41 |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | PI3K | 2.3 | effects of insulin and IGF-1 are mediated largely by PI3K/Akt PI3K Akt signaling ( 41 78 94 102 142 188 223 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | of insulin and IGF-1 are mediated largely by PI3K/Akt PI3K Akt signaling ( 41 78 94 102 142 188 223 234 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ( 41 78 94 102 142 188 223 234 and ANG II opposes insulin/IGF-1 insulin IGF-1 mediated signaling through this pathway |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | 142 188 223 234 and ANG II opposes insulin/IGF-1 insulin IGF-1 mediated signaling through this pathway ( 18 77 184 192 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | RAAS activation inhibits the beneficial metabolic effects of insulin and IGF-1 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II plays a seminal role in the genesis of cardiac |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II receptors have been characterized in cardiomyocytes and cardiac fibroblasts |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Although both AT 1 Rs and ANG II type 2 (AT AT 2 receptors (AT AT 2 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | and coronary vessel tissue most of the adverse effects of ANG II on hypertrophy fibrosis and left ventricular dysfunction are mediated |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | data suggesting that many of the detrimental effects of both ANG II and aldosterone are triggered by redox cycling of ROS |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | In cardiomyocytes ANG II stimulates phagocytic-type NADPH oxidase which is composed of a |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | p40 | 2.4 | of a membrane-bound p22 heterodimer and four regulatory subunits (p40 p40 p47 p67 and Nox2 and the small-molecular-weight G protein Rac1 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 1.3 | a membrane-bound p22 heterodimer and four regulatory subunits (p40 p40 p47 p67 and Nox2 and the small-molecular-weight G protein Rac1 ( |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 | 0.3 | membrane-bound p22 heterodimer and four regulatory subunits (p40 p40 p47 p67 and Nox2 and the small-molecular-weight G protein Rac1 ( 37 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 1.0 | heterodimer and four regulatory subunits (p40 p40 p47 p67 and Nox2 and the small-molecular-weight G protein Rac1 ( 37 130 136 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | p40 p47 p67 and Nox2 and the small-molecular-weight G protein Rac1 ( 37 130 136 138 |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.0 | stimulates phagocytic-type NADPH oxidase which is composed of a membrane-bound p22 heterodimer and four regulatory subunits (p40 p40 p47 p67 and |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II activation of the NADPH oxidase enzyme affects cell signaling |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | a recent investigation ( 231 it was hypothesized that chronic ANG II overexpression in the heart was associated with structural and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | with either an AT 1 R blocker or a SOD/catalase SOD catalase mimetic in a rodent model of chronically elevated tissue |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | in a rodent model of chronically elevated tissue levels of ANG II the transgenic TG(mRen2)27 TG mRen2 27 rat (Ren2) Ren2 |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | Nox2 | 1.0 | NADPH oxidase activity and immunostaining of NADPH oxidase subunits p22 Nox2 and Rac1 were significantly increased in the Ren2 rat in |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | activity and immunostaining of NADPH oxidase subunits p22 Nox2 and Rac1 were significantly increased in the Ren2 rat in conjunction with |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.1 | Membrane NADPH oxidase activity and immunostaining of NADPH oxidase subunits p22 Nox2 and Rac1 were significantly increased in the Ren2 rat |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | abrogated by both the AT 1 R blockade and SOD/catalase SOD catalase mimetic highlighting the role of ANG II in the |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | blockade and SOD/catalase SOD catalase mimetic highlighting the role of ANG II in the activation of NADPH oxidase and the importance |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | model previous studies ( 7 109 113 have shown that ANG II increases ROS in cultured myocardial fibroblasts and cardiomyocytes |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Indeed insulin-stimulated Akt phosphorylation/activation phosphorylation activation is significantly suppressed in Ren2 myocardial tissue |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | significantly suppressed in Ren2 myocardial tissue and inversely correlated to Rac1 expression and NADPH oxidase activity ( 231 |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | In the heart Akt activation is critical for the proper regulation of proteins responsible |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Akt activity in the heart is regulated by nutritional status insulin |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Optimal Akt signaling while important for physiological growth impedes pathological cardiac hypertrophy |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Akt | 0.8 | Restored Akt activation/phosphorylation, activation phosphorylation along with abrogation of cardiac hypertrophy and |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | treatment with either the AT 1 R blockade or SOD/catalase SOD catalase mimetic |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | oxidative stress and remodeling in the Ren2 model of chronic ANG II overexpression using the novel nonpeptide renin inhibitor aliskiren (Cooper |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Renin is the rate-limiting step in the generation of ANG II ( 148 158 232 thus renin inhibition should reduce |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ( 148 158 232 thus renin inhibition should reduce tissue ANG II levels as well as abrogate any direct renin effects |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Thus the reduction of ANG II levels via direct renin inhibition is of potential therapeutic |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 1.3 | activity as evidenced by increased immunostaining for the NADPH subunits p47 and Rac1 as well as 3-nitrotyrosine |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | evidenced by increased immunostaining for the NADPH subunits p47 and Rac1 as well as 3-nitrotyrosine |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | Translocation of the small GTP-binding protein Rac1 and p47 to the cell membrane is necessary for the |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 1.3 | Translocation of the small GTP-binding protein Rac1 and p47 to the cell membrane is necessary for the assembly and |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | activation of NADPH oxidase which has been directly implicated in ANG II-induced cardiac hypertrophy ( 3 19 50 3-Nitrotyrosine resulting from |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 1.6 | of myocardial oxidative stress as evidenced by decreased immunostaining for Rac1 and NADPH subunit p47 as well as 3-nitrotyrosine |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 1.3 | as evidenced by decreased immunostaining for Rac1 and NADPH subunit p47 as well as 3-nitrotyrosine |
| 3327 | ELN | elastin (supravalvular aortic stenosis, Williams-Beuren syndrome) | elastin | 1.0 | were evaluated by Verhoeff-van Gieson staining which is specific for elastin collagen connective tissue and nuclei |
| 2197 | COL1A1 | collagen, type I, alpha 1 | collagen | 0.3 | evaluated by Verhoeff-van Gieson staining which is specific for elastin collagen connective tissue and nuclei |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | There is accumulating evidence that ANG II and mineralocorticoids have interactive effects on the vasculature ( |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Mineralocorticoids upregulate ANG II receptors in VSMCs ( 211 and signaling of ANG |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | ANG II receptors in VSMCs ( 211 and signaling of ANG II is amplified by exposure to mineralocorticoids ( 210 211 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | Both ANG II and aldosterone stimulate vascular growth and remodeling ( 82 |
| 6871 | MAPK1 | mitogen-activated protein kinase 1 | MAPK | 2.4 | growth and remodeling ( 82 116 121 perhaps mediated through MAPK and ROS signaling ( 116 121 155 |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | although the effects of mineralocorticoids alone and in conjunction with ANG II on insulin signaling in vascular tissue remain to be |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ANG | 0.6 | R signaling by enhancing the cardiac oxidative stress induced by ANG II ( 90 93 196 238 |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | and glucocorticoid receptor antagonism and their impact on insulin and IGF-1 signaling in cardiovascular tissue |
| 5464 | IGF1 | insulin-like growth factor 1 (somatomedin C) | IGF-1 | 1.2 | summary activation of the RAAS contributes to altered insulin/IGF-1 insulin IGF-1 signaling pathways that lead to ROS formation endothelial dysfunction and |
| 6081 | INS | insulin | insulin | 1.0 | a : vascular effects of insulin ins /igf 1 and counteregulatory effects of angiotensin ii ang ii type 1 receptor at 1 r and mineralocorticoid receptor mr activation in endothelial cells. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | a : vascular effects of insulin ins /igf 1 and counteregulatory effects of angiotensin ii ang ii type 1 receptor at 1 r and mineralocorticoid receptor mr activation in endothelial cells. |
| 7979 | NR3C2 | nuclear receptor subfamily 3, group C, member 2 | mineralocorticoid receptor | 1.0 | a : vascular effects of insulin ins /igf 1 and counteregulatory effects of angiotensin ii ang ii type 1 receptor at 1 r and mineralocorticoid receptor mr activation in endothelial cells. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | angiotensin ii | 1.0 | a : vascular effects of insulin ins /igf 1 and counteregulatory effects of angiotensin ii ang ii type 1 receptor at 1 r and mineralocorticoid receptor mr activation in endothelial cells. |
| 6081 | INS | insulin | insulin | 1.0 | insulin actions on the blood vessel are partially mediated by increased production of nitric oxide no through phosphorylation and secondary activation of endothelial no synthase enos . |
| 6081 | INS | insulin | insulin | 1.0 | at 1 r activation decreases the availability of no via the induction of insulin resistance diminishing enos mrna stability and promoting nadph oxidase induced ros production. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | at 1 r activation decreases the availability of no via the induction of insulin resistance diminishing enos mrna stability and promoting nadph oxidase induced ros production. |
| 8975 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | phosphatidylinositol 3 kinase | 1.0 | d response element; g q g alpha q subunit; irs insulin receptor substrate; nox2 catalytic subunit of nadph oxidase; p22 p47 p40 and p67 subunits of nadph oxidase; ph pleckstrin homology domain; pi3 k phosphatidylinositol 3 kinase; pip phosphatidylinositol phosphate; pip2 phosphatidylinositol bisphosphate; pip3 phosphatidylinositol 3 4 5 trisphosphate; rok rho kinase; sod superoxide dismutase. |
| 6091 | INSR | insulin receptor | insulin receptor | 1.0 | akt pkb; gre glucocorticoid response element; g q g alpha q subunit; irs insulin receptor substrate; nox2 catalytic subunit of nadph oxidase; p22 p47 p40 and p67 subunits of nadph oxidase; ph pleckstrin homology domain; pi3 k phosphatidylinositol 3 kinase; pip phosphatidylinositol phospha |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | akt pkb; gre glucocorticoid response element; g q g alpha q subunit; irs insulin receptor substrate; nox2 catalytic subunit of nadph oxidase; p22 p47 p40 and p67 subunits of nadph oxidase; ph pleckstrin homology domain; pi3 k phosphatidylinositol 3 kinase; pip phosphatidylinositol phosphate; pip2 phosphatidylinositol bisphosphate; pip3 phosphatidylinositol 3 4 5 trisphosphate; rok rho |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | in homology domain; pi3 k phosphatidylinositol 3 kinase; pip phosphatidylinositol phosphate; pip2 phosphatidylinositol bisphosphate; pip3 phosphatidylinositol 3 4 5 trisphosphate; rok rho kinase; sod superoxide dismutase. |
| 4390 | GNAQ | guanine nucleotide binding protein (G protein), q polypeptide | g alpha q | 1.0 | akt pkb; gre glucocorticoid response element; g q g alpha q subunit; irs insulin receptor substrate; nox2 catalytic subunit of nadph oxidase; p22 p47 p40 and p67 subunits of nadph oxidase; ph pleckstrin homology domain; pi3 k phosphatidylinositol 3 kinase; pi |
| 6081 | INS | insulin | insulin | 1.0 | b : opposing effects of ang ii and aldosterone aldo versus insulin/igf 1 on vascular smooth muscle cells vsmcs . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | b : opposing effects of ang ii and aldosterone aldo versus insulin/igf 1 on vascular smooth muscle cells vsmcs . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 cause vsmc relaxation whereas ang ii and mineralocorticoids cause contraction. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | insulin and igf 1 cause vsmc relaxation whereas ang ii and mineralocorticoids cause contraction. |
| 29826 | MYLK3 | myosin light chain kinase 3 | mlc kinase | 1.0 | mbs myosin bound serine; mlc myosin light chain; mlck mlc kinase; na/ca exch na /ca exchanger. |
| 6081 | INS | insulin | insulin | 1.0 | functional and metabolic effects of insulin and igf 1 in the heart. |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 modulate glucose transport glycogen synthesis lipid metabolism growth contractility and apoptosis in cardiomyocytes. |
| 6081 | INS | insulin | insulin | 1.0 | upon activation of the mitogen activated protein map kinase pathway insulin/igf 1 and ang ii/aldosterone signaling may converge to cause deleterious effects on cardiovascular tissue. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | upon activation of the mitogen activated protein map kinase pathway insulin/igf 1 and ang ii/aldosterone signaling may converge to cause deleterious effects on cardiovascular tissue. |
| 17937 | CUZD1 | CUB and zona pellucida-like domains 1 | erg 1 | 1.0 | ap 1 activating protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor protein; glut4 glucose transporter 4. |
| 4910 | HIF1A | hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) | hypoxia inducible factor 1 | 1.0 | ap 1 activating protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor protein; glut4 glucose transporter 4. |
| 4910 | HIF1A | hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) | hif 1 | 1.0 | ap 1 activating protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor protein; glut4 glucose transporter 4. |
| 3796 | FOS | v-fos FBJ murine osteosarcoma viral oncogene homolog | ap 1 | 1.0 | ap 1 activating protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor pro |
| 3238 | EGR1 | early growth response 1 | early growth response 1 | 1.0 | ap 1 activating protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor protein; glut4 glucose transporter 4. |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | glucose transporter 4 | 1.0 | protein 1; crk protein exhibiting the src homology 2 sh2 domain; erg 1 early growth response 1 gene; hif 1 hypoxia inducible factor 1; sch phosphotyrosine adaptor molecule; sck adaptor protein; glut4 glucose transporter 4. |
| 6081 | INS | insulin | insulin | 1.0 | ang ii and aldosterone/corticosterone antagonism to metabolic actions of insulin/igf 1 in skeletal muscle. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii and aldosterone/corticosterone antagonism to metabolic actions of insulin/igf 1 in skeletal muscle. |
| 6081 | INS | insulin | insulin | 1.0 | at 1 r activation impaired insulin signaling in skeletal muscle with a consequent reduction in glucose uptake. |
| 6091 | INSR | insulin receptor | insulin receptor | 1.0 | possible mechanisms involved in skeletal muscle insulin resistance include inadequate interaction between the insulin receptor and irs serine phosphorylation of irs lack of phosphorylation of key tyrosine residues in irs and reduced activation of akt. |
| 6081 | INS | insulin | insulin | 1.0 | through the activation of nadph oxidase aldosterone can increase oxidative stress and impair metabolic insulin signaling. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | through the activation of nadph oxidase aldosterone can increase oxidative stress and impair metabolic insulin signaling. |
| 6081 | INS | insulin | insulin | 1.0 | activation of the renin angiotensin aldosterone system induces vascular oxidative stress and insulin resistance. |
| 9958 | REN | renin | renin | 1.0 | activation of the renin angiotensin aldosterone system induces vascular oxidative stress and insulin resistance. |
| 6081 | INS | insulin | insulin | 1.0 | vascular superoxide generation was detected by dihydroethidium dhe immunostaining in the insulin resistant transgenic tg mren2 27 ren2 rat which overexpresses the renin gene with subsequent elevated tissue levels of ang ii relative to sprague dawley sd control. |
| 9958 | REN | renin | renin | 1.0 | vascular superoxide generation was detected by dihydroethidium dhe immunostaining in the insulin resistant transgenic tg mren2 27 ren2 rat which overexpresses the renin gene with subsequent elevated tissue levels of ang ii relative to sprague dawley sd control. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ide generation was detected by dihydroethidium dhe immunostaining in the insulin resistant transgenic tg mren2 27 ren2 rat which overexpresses the renin gene with subsequent elevated tissue levels of ang ii relative to sprague dawley sd control. |
| 3327 | ELN | elastin (supravalvular aortic stenosis, Williams-Beuren syndrome) | elastin | 1.0 | the green autofluorescence is specific for elastin fibers. |
| 6081 | INS | insulin | insulin | 1.0 | micro positron emission tomograph pet and electrocardiographically gated magnetic resonance images mri of sd animals with and without insulin/glucose stimulation. |
| 6081 | INS | insulin | insulin | 1.0 | upon insulin/glucose stimulation there was increased myocardial glucose uptake noted by increased brightness compared with the basal state. |
| 6081 | INS | insulin | insulin | 1.0 | hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. |
| 6081 | INS | insulin | insulin | 1.0 | insulin resistance plays a significant role in the relationship between hypertension type 2 diabetes mellitus chronic kidney disease and cardiovascular disease. |
| 6081 | INS | insulin | insulin | 1.0 | there is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues i.e. skeletal muscle liver and adipose tissue . |
| 6081 | INS | insulin | insulin | 1.0 | activation of the renin angiotensin aldosterone system and subsequent elevations in angiotensin ii and aldosterone as seen in cardiometabolic syndrome contribute to altered insulin/igf 1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. |
| 9958 | REN | renin | renin | 1.0 | activation of the renin angiotensin aldosterone system and subsequent elevations in angiotensin ii and aldosterone as seen in cardiometabolic syndrome contribute to altered insulin/igf 1 signaling pathways and reactive oxyg |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | angiotensin ii | 1.0 | activation of the renin angiotensin aldosterone system and subsequent elevations in angiotensin ii and aldosterone as seen in cardiometabolic syndrome contribute to altered insulin/igf 1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular d |
| 6081 | INS | insulin | insulin | 1.0 | this review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue. |
| 6081 | INS | insulin | insulin | 1.0 | hypertension is present in ~30% of the adult united states population and often occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome cms 29 115 163 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | according to recent data up to 70 million americans have insulin resistance which plays a significant role in the relationship between hypertension type 2 diabetes mellitus chronic kidney disease ckd and cardiovascular cv disease cvd 69 . |
| 6081 | INS | insulin | insulin | 1.0 | there is accumulating evidence that insulin resistance occurs in cv and renal tissue as well as in classical metabolic tissues i.e. skeletal muscle liver and adipose tissue 125 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | this review focuses on currently accepted mechanisms underlying the development of resistance to the metabolic actions of insulin in cv tissue see figs 1 and 2 as well as skeletal muscle tissues 27 190 see fig 3 . |
| 6081 | INS | insulin | insulin | 1.0 | normal actions of insulin in cv tissue |
| 6081 | INS | insulin | insulin | 1.0 | both insulin and igf 1 receptors exist in cv tissue 186 . |
| 6091 | INSR | insulin receptor | insulin receptor | 1.0 | activation of the insulin receptor ir and igf 1 receptor ligand activated transmembrane receptors with tyrosine kinase activity phosphorylates intracellular substrates including ir substrate irs family members and shc which in turn se |
| 8816 | PDPK1 | 3-phosphoinositide dependent protein kinase-1 | 3 phosphoinositide dependent protein kinase 1 | 1.0 | this molecule then binds to the pleckstrin homology domain in 3 phosphoinositide dependent protein kinase 1 pdk 1 resulting in its phosphorylation and the activation of other downstream serine threonine kinases including pkb akt and atypical pkc isoforms which mediate a number of metabolic actions includin |
| 11009 | SLC2A4 | solute carrier family 2 (facilitated glucose transporter), member 4 | glucose transporter 4 | 1.0 | dk 1 resulting in its phosphorylation and the activation of other downstream serine threonine kinases including pkb akt and atypical pkc isoforms which mediate a number of metabolic actions including glucose transporter 4 glut4 translocation to the membrane leading to glucose uptake in myocardial tissue and skeletal muscle as well as nitric oxide no production in blood vessels 125 186 190 202 . |
| 6081 | INS | insulin | insulin | 1.0 | growth and remodeling responses to insulin and igf 1 generally involves both stat and mapk signaling pathways. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | cross talk from signaling pathways of heterologous receptors such as the ang ii type 1 at 1 receptor at 1 r exert enhancing effects on this growth/remodeling signaling pathways while interfering with the metabolic signaling pathway 186 190 202 . |
| 6081 | INS | insulin | insulin | 1.0 | tyrosine phosphatases which dephosphorylate ir and the igf 1 receptor as well as lipid phosphatases i.e. ship 2 and pten which dephosphorylate pi 3 4 5 p 3 are involved in the negative regulation of insulin and igf 1 signaling pathways 220 . |
| 6081 | INS | insulin | insulin | 1.0 | inappropriate activation of these phosphatases may contribute to insulin/igf 1 resistance in cv tissue as well as liver skeletal muscle and adipose tissue 27 202 220 . |
| 6081 | INS | insulin | insulin | 1.0 | vascular actions of insulin/igf 1 |
| 6081 | INS | insulin | insulin | 1.0 | vascular relaxation effects of insulin/igf 1 are mediated in part by endothelial cell production of no 186 190 224 235 236 fig 1 a . |
| 6081 | INS | insulin | insulin | 1.0 | this insulin mediated activation requires the formation of a ternary enos heat shock protein 90 hsp90 akt complex 125 199 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 also increase vascular smooth muscle cell vsmc production of no 13 125 188 . |
| 6081 | INS | insulin | insulin | 1.0 | thus insulin and igf 1 promote vascular relaxation in part via increases in no bioavailability. |
| 6081 | INS | insulin | insulin | 1.0 | insulin also promotes vascular relaxation by attenuating agonist i.e. ang ii induced increases in cytosolic calcium [ca ] and myosin light chain mlc kinase activity 13 174 191 . |
| 29826 | MYLK3 | myosin light chain kinase 3 | mlc kinase | 1.0 | insulin also promotes vascular relaxation by attenuating agonist i.e. ang ii induced increases in cytosolic calcium [ca ] and myosin light chain mlc kinase activity 13 174 191 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | insulin also promotes vascular relaxation by attenuating agonist i.e. ang ii induced increases in cytosolic calcium [ca ] and myosin light chain mlc kinase activity 13 174 191 . |
| 6081 | INS | insulin | insulin | 1.0 | by enhancing mlc phosphatase activity insulin and igf 1 reduce mlc kinase activity and thus [ca ] sensitive contraction 13 125 174 191 199 fig 1 b . |
| 29826 | MYLK3 | myosin light chain kinase 3 | mlc kinase | 1.0 | by enhancing mlc phosphatase activity insulin and igf 1 reduce mlc kinase activity and thus [ca ] sensitive contraction 13 125 174 191 199 fig 1 b . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii actions on the vasculature |
| 6081 | INS | insulin | insulin | 1.0 | there is accumulating evidence that ang ii in addition to its vasoconstriction effects attenuates the cvand skeletal muscle metabolic actions of insulin and igf 1 115 186 190 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | there is accumulating evidence that ang ii in addition to its vasoconstriction effects attenuates the cvand skeletal muscle metabolic actions of insulin and igf 1 115 186 190 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | the mechanisms involved in these inhibitory effects of ang ii include the generation of ros and the activation of small molecular weight proteins such as rhoa and rac1 9 66 189 190 figs 1 and 2 . |
| 6081 | INS | insulin | insulin | 1.0 | indeed there is increasing evidence indicating that ang ii contributes to insulin resistance and other components of cms such as hypertension dyslipidemia central fat deposition hepatic steatosis ckd and proteinuria 69 77 186 190 194 229 230 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | indeed there is increasing evidence indicating that ang ii contributes to insulin resistance and other components of cms such as hypertension dyslipidemia central fat deposition hepatic steatosis ckd and proteinuria 69 77 186 190 194 229 230 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii exerts inflammatory effects and promotes vascular growth/remodeling apoptosis and fibrosis. |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | mcp 1 | 1.0 | ros activate transcription factors such as tnf alpha monocyte chemoattractant protein mcp 1 il 6 and c reactive protein crp . |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | ros activate transcription factors such as tnf alpha monocyte chemoattractant protein mcp 1 il 6 and c reactive protein crp . |
| 2367 | CRP | C-reactive protein, pentraxin-related | c reactive protein | 1.0 | ros activate transcription factors such as tnf alpha monocyte chemoattractant protein mcp 1 il 6 and c reactive protein crp . |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | il 6 | 1.0 | ros activate transcription factors such as tnf alpha monocyte chemoattractant protein mcp 1 il 6 and c reactive protein crp . |
| 6081 | INS | insulin | insulin | 1.0 | tnf alpha in turn impedes insulin and igf 1 mediated enos activation as well as the antiapoptotic actions of insulin and igf 1 128 186 190 . |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | tnf alpha in turn impedes insulin and igf 1 mediated enos activation as well as the antiapoptotic actions of insulin and igf 1 128 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | animal model to investigate the role of ang ii in mediating insulin/igf 1 resistance |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | animal model to investigate the role of ang ii in mediating insulin/igf 1 resistance |
| 6081 | INS | insulin | insulin | 1.0 | one system raas with increased ang ii levels and increased plasma mineralocorticoids to evaluate the role of increased tissue ang ii and mineralocorticoids in mediating cvd as well as skeletal muscle insulin resistance fig 3 18 229 231 . |
| 9958 | REN | renin | renin | 1.0 | our laboratory has utilized the transgenic tg mren2 27 rat which harbors the mouse renin gene and displays an activated tissue renin angiotensin aldosterone system raas with increased ang ii levels and increased plasma mineralocorticoids to evaluate the role of increased tissue ang ii and mineralocorticoids in mediating cvd as wel |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | our laboratory has utilized the transgenic tg mren2 27 rat which harbors the mouse renin gene and displays an activated tissue renin angiotensin aldosterone system raas with increased ang ii levels and increased plasma mineralocorticoids to evaluate the role of increased tissue ang ii and mineralocorticoids in mediating cvd as well as skeletal muscle insulin resistance fig 3 18 229 231 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | levels and increased plasma mineralocorticoids to evaluate the role of increased tissue ang ii and mineralocorticoids in mediating cvd as well as skeletal muscle insulin resistance fig 3 18 229 231 . |
| 6081 | INS | insulin | insulin | 1.0 | indeed this rodent model develops proteinuria 77 231 as well as insulin resistance 18 fatty liver steatosis and hypertension 18 77 229 231 making it a relevant model of cms. |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | study 230 from our laboratory has observed that the vasculature from young ren2 rats exhibits increased nadph oxidase activity ros levels fig 4 lipid peroxidation inflammation increased expression of tnf alpha and crp and indexes of apoptosis compared with sprague dawley rats. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | a recent study 230 from our laboratory has observed that the vasculature from young ren2 rats exhibits increased nadph oxidase activity ros levels fig 4 lipid peroxidation inflammation increased expression of tnf alpha and crp and indexes of apoptosis compared with sprague dawley rats. |
| 6081 | INS | insulin | insulin | 1.0 | furthermore in the vasculature there was a marked reduction in insulin stimulation of akt signaling enos ser phosphorylation/activation. |
| 1516 | CAT | catalase | catalase | 1.0 | these abnormalities were markedly improved by in vivo treatment with an at 1 r blocker or the superoxide dismutase sod /catalase minetic tempol. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | these abnormalities were markedly improved by in vivo treatment with an at 1 r blocker or the superoxide dismutase sod /catalase minetic tempol. |
| 6081 | INS | insulin | insulin | 1.0 | available data have suggested that vascular raas activation and insulin/igf 1 resistance perpetuate each other and concordantly contribute to endothelial dysfunction vascular inflammation/remodeling and hypertension 230 . |
| 6081 | INS | insulin | insulin | 1.0 | similar observations have also been made in the left ventricle of hearts taken from young insulin resistant ren2 rats 192 231 ; cooper sa whaley connell a habibi j stump cs link cd hayden mr ferrario c sowers jr unpublished observations . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and ang ii in the heart |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | insulin and ang ii in the heart |
| 6081 | INS | insulin | insulin | 1.0 | insulin regulates metabolism in cv tissue by modulating glucose uptake and utilization glycogen synthesis lipid metabolism proliferation contractility remodeling and apoptosis in cardiomyocytes fig 2 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 exert a number of metabolic and functional effects on the heart 2 22 62 64 70 84 98 105 117 137 146 153 163 165 179 180 192 198 222 ; cooper sa et al. unpublished observations fig 2 . |
| 6081 | INS | insulin | insulin | 1.0 | as in skeletal muscle glucose uptake in cardiomyocytes involves mobilization of insulin responsive glut4 via a pi3k/akt signaling pathway 2 98 fig 2 . |
| 6081 | INS | insulin | insulin | 1.0 | furthermore in cardiomyocytes insulin stimulation of the pi3k/akt pathway results in the phosphorylation and nuclear exclusion of the forkhead transcription factor foxo 1 which further modulates glucose and lipid metabolism 125 137 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 normally enhance cardiac contractility 22 153 163 165 186 190 via signaling through the pi3k/akt pathway. |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 also enhance cardiomyocyte myofilament ca sensitivity 42 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 induced increases in myocardial contractility result in increased oxygen consumption 198 . |
| 6081 | INS | insulin | insulin | 1.0 | cardiac oxygen demand is a potent determinant of myocardial blood flow mbf and insulin and igf 1 enhance mbf and promote capillary recruitment in the heart 84 198 . |
| 6081 | INS | insulin | insulin | 1.0 | these observations suggest coupling between the metabolic and coronary vascular actions of insulin and igf 1 in the heart with increases in capillary recruitment and mbf enhancing insulin stimulated increases in the delivery of insulin and glucose. |
| 6081 | INS | insulin | insulin | 1.0 | stimulated increases in the delivery of insulin and glucose. |
| 6081 | INS | insulin | insulin | 1.0 | these actions of insulin and igf 1 as well as their direct effects on cardiomyocytes also enhance glucose transport 2 98 137 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 also regulate developmental and physiological growth and remodeling of the heart 41 78 94 102 142 163 223 234 fig 2 . |
| 4617 | GSK3B | glycogen synthase kinase 3 beta | glycogen synthase kinase 3 beta | 1.0 | downstream from akt activation of the mammalian target of rapamycin promotes cardiac growth whereas suppression of glycogen synthase kinase 3 beta as well as foxo phosphorylation also modulates cardiomyocyte growth 78 223 . |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl 2 | 1.0 | insulin and igf 1 also promote survival by direct phosphorylation/inactivation of bad a member of the bcl 2 family which promotes apoptosis by binding to and antagonizing the action of prosurvival members of the family such as bcl 2 and bcl xl. |
| 990 | BCL2 | B-cell CLL/lymphoma 2 | bcl 2 | 1.0 | family which promotes apoptosis by binding to and antagonizing the action of prosurvival members of the family such as bcl 2 and bcl xl. |
| 992 | BCL2L1 | BCL2-like 1 | bcl xl | 1.0 | al by direct phosphorylation/inactivation of bad a member of the bcl 2 family which promotes apoptosis by binding to and antagonizing the action of prosurvival members of the family such as bcl 2 and bcl xl. |
| 6081 | INS | insulin | insulin | 1.0 | insulin and igf 1 also promote survival by direct phosphorylation/inactivation of bad a member of the bcl 2 family which promotes apoptosis by binding to and antagonizing the action of prosurvival members of |
| 6081 | INS | insulin | insulin | 1.0 | insulin/igf 1 activation of akt may also interfere with stress activated protein kinases such as jnk p38 and mapk pathways critically involved in the induction of apoptosis following exposure of cardiomyocyt |
| 1876 | CFLAR | CASP8 and FADD-like apoptosis regulator | c flip | 1.0 | finally akt activation increases the expression of c flip a caspase 8 homologene that inhibits tnf receptor family induced apoptosis 142 . |
| 1509 | CASP8 | caspase 8, apoptosis-related cysteine peptidase | caspase 8 | 1.0 | finally akt activation increases the expression of c flip a caspase 8 homologene that inhibits tnf receptor family induced apoptosis 142 . |
| 6081 | INS | insulin | insulin | 1.0 | in conditions of insulin resistance/hyperinsulinemia pathological cardiomyocyte hypertrophy is promoted by interactions of insulin/igf 1 with growth factors such as ang ii catecholamines endothelin and mineralocorticoids to stimulate signaling pathways involving mapk p38 mapk jak/stat and the small molecular weight g proteins rh |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | in conditions of insulin resistance/hyperinsulinemia pathological cardiomyocyte hypertrophy is promoted by interactions of insulin/igf 1 with growth factors such as ang ii catecholamines endothelin and mineralocorticoids to stimulate signaling pathways involving mapk p38 mapk jak/stat and the small molecular weight g proteins rho and ras 163 180 186 188 190 . |
| 6081 | INS | insulin | insulin | 1.0 | insulin resistance and cvd: role of raas and other factors |
| 6081 | INS | insulin | insulin | 1.0 | clinical evidence supports a link between insulin resistance/hyperinsulinemia and hypertension including positive associations between blood pressure and fasting insulin levels in patients with essential hypertension 42 118 162 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | mechanisms to explain this linkage include cellular abnormalities in insulin signaling 186 190 cellular cation alterations enhanced sympathetic nervous system activity 162 and enhanced raas activity 186 190 as well as inflammation and oxidative stress 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | importantly resistance to the metabolic and proliferative actions of insulin appears to be differential. |
| 6081 | INS | insulin | insulin | 1.0 | indeed a seminal feature of insulin resistance is impairment in pi3k/akt signaling metabolic pathways whereas other insulin signaling growth pathways including ras/mapk/jak/stat signaling are not inhibited 36 89 150 186 190 . |
| 6081 | INS | insulin | insulin | 1.0 | in addition proinflammatory effects of chronically elevated levels of glucose and fatty acids contribute to endothelial dysfunction chronic low grade inflammation and insulin resistance. |
| 6081 | INS | insulin | insulin | 1.0 | for example exposure of the vasculature and myocardium to elevated levels of free fatty acids leads to impaired insulin signaling 47 226 enhancement of vascular raas 227 and oxidative stress 83 as well as impaired insulin stimulated enos activity and no production 47 . |
| 6081 | INS | insulin | insulin | 1.0 | signaling 47 226 enhancement of vascular raas 227 and oxidative stress 83 as well as impaired insulin stimulated enos activity and no production 47 . |
| 6081 | INS | insulin | insulin | 1.0 | increased ros induced by hyperglycemia and dyslipidemia further impair insulin signaling decrease no bioavailability reduce cellular tetrohydrobiopterin levels and promote the generation of superoxide by enos. |
| 6081 | INS | insulin | insulin | 1.0 | role of raas in vascular insulin resistance |
| 6081 | INS | insulin | insulin | 1.0 | as noted previously physiological concentrations of insulin increase vasodilatation through no release and exert antioxidant and anti inflammatory effects via signaling through the pi3k/akt metabolic pathway 186 190 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii and mineralocorticoids in contrast cause vasoconstriction and enhance the expression of proinflammatory cytokines adhesion molecules growth and inflammatory pathways 80 85 86 135 153 192 207 208 . |
| 6081 | INS | insulin | insulin | 1.0 | furthermore ang ii and aldosterone interfere with many of the metabolic signaling actions of insulin and igf 1 in the cv system 9 80 85 86 102 135 153 186 188 190 207 208 230 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | furthermore ang ii and aldosterone interfere with many of the metabolic signaling actions of insulin and igf 1 in the cv system 9 80 85 86 102 135 153 186 188 190 207 208 230 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii acting through the at 1 r increases the generation of ros in the vasculature primarily through activation of the membrane bound nadph oxidase enzyme complex fig 1 a and b 8 16 31 57 63 101 112 141 15 |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | ang ii acting through the at 1 r increases the generation of ros in the vasculature primarily through activation of the membrane bound nadph oxidase enzyme complex fig 1 a and b 8 16 31 57 63 101 112 141 155 159 189 201 206 213 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | infusion of ang ii impairs endothelium dependent vasorelaxation 31 and this impairment is corrected by coadministration of sod 105 indicating the critical role of ros in ang ii mediated endothelial dysfunction 189 . |
| 6081 | INS | insulin | insulin | 1.0 | ang ii stimulated ros inhibit insulin/igf 1 signaling through the pi3k/akt signaling pathway to activate enos 13 125 199 224 235 236 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii stimulated ros inhibit insulin/igf 1 signaling through the pi3k/akt signaling pathway to activate enos 13 125 199 224 235 236 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | furthermore ros generated by ang ii inactivate no 20 120 152 203 and the resultant decrease in bioavailable no in turn upregulates the at 1 r on vascular cells 81 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | this creates a cycle of impaired endothelium derived vasodilation and increased ang ii mediated vasoconstriction. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii also stimulates rhoa/rho kinase activation which decreases enos expression in part by decreasing enos mrna stability 122 200 fig 1 a . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii acting via its at 1 r increases vsmc contraction by increasing intracellular [ca ] and ca mlc sensitization 129 233 fig 1 b . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | both processes are mediated in part by ang ii stimulated generation of ros in endothelial cells and vsmcs 189 205 233 . |
| 6081 | INS | insulin | insulin | 1.0 | ang ii also increases ca mlc sensitization by stimulating rho kinase activity in vsmcs whereas insulin and igf 1 induce relaxation by increasing endothelial cell production of no and by reducing ca mlc sensitization 175 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii also increases ca mlc sensitization by stimulating rho kinase activity in vsmcs whereas insulin and igf 1 induce relaxation by increasing endothelial cell production of no and by reducing ca mlc sens |
| 6081 | INS | insulin | insulin | 1.0 | ang ii decreases the ability of insulin and igf 1 to decrease ca mlc sensitization by activating rho kinase which phosphorylates myosin binding protein and thereby inhibits the ability of these peptides to dephosphorylate ca mlc which lead |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii decreases the ability of insulin and igf 1 to decrease ca mlc sensitization by activating rho kinase which phosphorylates myosin binding protein and thereby inhibits the ability of these peptides to |
| 6081 | INS | insulin | insulin | 1.0 | this concept is bourne out by the observation that increases in rho kinas and a decrease in myosin binding protein activity occurs in ang ii mediated 30 and insulin resistant 176 hypertensive rodents. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | this concept is bourne out by the observation that increases in rho kinas and a decrease in myosin binding protein activity occurs in ang ii mediated 30 and insulin resistant 176 hypertensive rodents. |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | mcp 1 | 1.0 | nf kappab in turn enhances other ang ii mediated inflammatory responses by upregulating other inflammatory molecules such as tnf alpha mcp 1 and crp 72 124 . |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | nf kappab in turn enhances other ang ii mediated inflammatory responses by upregulating other inflammatory molecules such as tnf alpha mcp 1 and crp 72 124 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | nf kappab in turn enhances other ang ii mediated inflammatory responses by upregulating other inflammatory molecules such as tnf alpha mcp 1 and crp 72 124 . |
| 5992 | IL1B | interleukin 1, beta | il 1 | 1.0 | tnf alpha activates several serine kinases including jnk i kappak beta and il 1 beta receptor associated kinase 91 which directly or indirectly increase serine phosphorylation of irs 1/2 leading to decreased pi3k/akt signaling responses and subsequent impaired insulin/igf 1 stim |
| 6081 | INS | insulin | insulin | 1.0 | ppak beta and il 1 beta receptor associated kinase 91 which directly or indirectly increase serine phosphorylation of irs 1/2 leading to decreased pi3k/akt signaling responses and subsequent impaired insulin/igf 1 stimulation of enos production of no and vasodilatation 6 51 95 96 . |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | tnf alpha activates several serine kinases including jnk i kappak beta and il 1 beta receptor associated kinase 91 which directly or indirectly increase serine phosphorylation of irs 1/2 leading to decreased p |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tnf alpha | 1.0 | tnf alpha increases the expression of other inflammatory substance including il 6 and crp. |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | il 6 | 1.0 | tnf alpha increases the expression of other inflammatory substance including il 6 and crp. |
| 6081 | INS | insulin | insulin | 1.0 | crp in turn appears to attenuate insulin stimulated no production in endothelial cells by increasing phosphorylation of irs 1 at ser and indirectly by enhancing rho kinase and jnk signaling 6 217 . |
| 6081 | INS | insulin | insulin | 1.0 | crp also upregulates vsmc at 1 rs 225 and increases the expression of vcam icam e selectin and mcp 1 in endothelial cells 144 thus counterbalancing the antiatherosclerotic and vasodilatory effects of insulin/igf 1 stimulated no production. |
| 10618 | CCL2 | chemokine (C-C motif) ligand 2 | mcp 1 | 1.0 | crp also upregulates vsmc at 1 rs 225 and increases the expression of vcam icam e selectin and mcp 1 in endothelial cells 144 thus counterbalancing the antiatherosclerotic and vasodilatory effects of insulin/igf 1 stimulated no production. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | in addition to stimulating membrane nadph oxidase in vascular cells ang ii in conjunction with other cellular stresses may increase endoplasmic reticulum stress 139 and mitochondrial oxidative stress 186 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | in addition to stimulating membrane nadph oxidase in vascular cells ang ii in conjunction with other cellular stresses may increase endoplasmic reticulum stress 139 and mitochondrial oxidative stress 186 . |
| 6081 | INS | insulin | insulin | 1.0 | nflammation may affect be contributing to adipose tissue inflammation increased macrophages 35 and nonalcoholic fatty liver disease 1 conditions frequently associated with alterations in the raas and insulin resistance 183 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | increased oxidative stress can also be accentuated by cu/zn sod deficiency in response to ang ii 43 45 . |
| 6081 | INS | insulin | insulin | 1.0 | effects of raas on cardiac insulin signaling structure and function |
| 6081 | INS | insulin | insulin | 1.0 | as previously noted insulin and igf 1 generally exert beneficial effects on myocardial mechanical electrical coupling and both diastolic and systolic function 22 62 64 84 105 117 146 153 163 165 179 180 198 222 . |
| 6081 | INS | insulin | insulin | 1.0 | many of these beneficial effects of insulin and igf 1 are mediated largely by pi3k/akt signaling 41 78 94 102 142 188 223 234 and ang ii opposes insulin/igf 1 mediated signaling through this pathway 18 77 184 192 194 229 231 ; cooper sa et al. unpublished observations fig 2 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | many of these beneficial effects of insulin and igf 1 are mediated largely by pi3k/akt signaling 41 78 94 102 142 188 223 234 and ang ii opposes insulin/igf 1 mediated signaling through this pathway 18 77 184 192 194 229 231 ; cooper sa et al. unpublished observations fig 2 . |
| 6081 | INS | insulin | insulin | 1.0 | there are several mechanisms whereby cardiac raas activation inhibits the beneficial metabolic effects of insulin and igf 1. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii plays a seminal role in the genesis of cardiac hypertrophy interstitial fibrosis and left ventricular dysfunction 34 46 65 146 172 173 178 204 216 219 fig 2 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii receptors have been characterized in cardiomyocytes and cardiac fibroblasts 34 146 172 173 216 219 as well as in the endothelial lining of coronary arteries 65 146 178 216 237 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | although both at 1 rs and ang ii type 2 at 2 receptors at 2 rs are present on cardiac and coronary vessel tissue most of the adverse effects of ang ii on hypertrophy fibrosis and left ventricular dysfunction are mediated through at 1 rs 146 237 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | there are increasing experimental data suggesting that many of the detrimental effects of both ang ii and aldosterone are triggered by redox cycling of ros generated by a membrane nadph oxidase dependent pathway as well as mitochondria generated ros 11 24 25 58 37 38 75 123 126 146 153 156 189 192 23 |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | there are increasing experimental data suggesting that many of the detrimental effects of both ang ii and aldosterone are triggered by redox cycling of ros generated by a membrane nadph oxidase dependent pathway as well as mitochondria generated ros 11 24 25 58 37 38 75 123 126 146 153 156 189 192 231 ; cooper sa et al. unpublished observations . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | in cardiomyocytes ang ii stimulates phagocytic type nadph oxidase which is composed of a membrane bound p22 heterodimer and four regulatory subunits p40 p47 p67 and nox2 and the small molecular weight g protein rac1 37 130 1 |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | in cardiomyocytes ang ii stimulates phagocytic type nadph oxidase which is composed of a membrane bound p22 heterodimer and four regulatory subunits p40 p47 p67 and nox2 and the small molecular weight g protein rac1 37 130 136 138 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | ang ii activation of the nadph oxidase enzyme affects cell signaling responses and facilitates cardiac remodeling and hypertrophy 11 24 38 153 as evidenced by the attenuation of these pathological effects f |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | ang ii activation of the nadph oxidase enzyme affects cell signaling responses and facilitates cardiac remodeling and hypertrophy 11 24 38 153 as evidenced by the attenuation of these pathological effects following treatment with free rad |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | in a recent investigation 231 it was hypothesized that chronic ang ii overexpression in the heart was associated with structural and functional abnormalities that are driven by nadph oxidase mediated generation of ros. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | in a recent investigation 231 it was hypothesized that chronic ang ii overexpression in the heart was associated with structural and functional abnormalities that are driven by nadph oxidase mediated generation of ros. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | this notion was evaluated by in vivo treatment with either an at 1 r blocker or a sod/catalase mimetic in a rodent model of chronically elevated tissue levels of ang ii the transgenic tg mren2 27 rat ren2 . |
| 1516 | CAT | catalase | catalase | 1.0 | this notion was evaluated by in vivo treatment with either an at 1 r blocker or a sod/catalase mimetic in a rodent model of chronically elevated tissue levels of ang ii the transgenic tg mren2 27 rat ren2 . |
| 6081 | INS | insulin | insulin | 1.0 | results of this investigation indicated that the hypertensive insulin resistant ren2 rat manifests increased oxidative stress in concert with structural and functional changes in the heart. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | membrane nadph oxidase activity and immunostaining of nadph oxidase subunits p22 nox2 and rac1 were significantly increased in the ren2 rat in conjunction with increased levels of myocardial tissue oxidative stress. |
| 2422 | CS | citrate synthase | citrate synthase | 1.0 | citrate synthase activity and transmission electron microscopy demonstrated significant increases in mitochondrial numbers in ren2 left ventricle tissue. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | these effects were abrogated by both the at 1 r blockade and sod/catalase mimetic highlighting the role of ang ii in the activation of nadph oxidase and the importance of ros in cardiac remodeling and dysfunction. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | these effects were abrogated by both the at 1 r blockade and sod/catalase mimetic highlighting the role of ang ii in the activation of nadph oxidase and the importance of ros in cardiac remodeling and dysfunction. |
| 1516 | CAT | catalase | catalase | 1.0 | these effects were abrogated by both the at 1 r blockade and sod/catalase mimetic highlighting the role of ang ii in the activation of nadph oxidase and the importance of ros in cardiac remodeling and dysfunction. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | while the observations are novel in the ren2 model previous studies 7 109 113 have shown that ang ii increases ros in cultured myocardial fibroblasts and cardiomyocytes. |
| 6081 | INS | insulin | insulin | 1.0 | indeed insulin stimulated akt phosphorylation/activation is significantly suppressed in ren2 myocardial tissue and inversely correlated to rac1 expression and nadph oxidase activity 231 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | indeed insulin stimulated akt phosphorylation/activation is significantly suppressed in ren2 myocardial tissue and inversely correlated to rac1 expression and nadph oxidase activity 231 . |
| 6081 | INS | insulin | insulin | 1.0 | akt activity in the heart is regulated by nutritional status insulin pressure overload and redox status 5 32 41 182 . |
| 1516 | CAT | catalase | catalase | 1.0 | tivation/phosphorylation along with abrogation of cardiac hypertrophy and dysfunction were observed following reductions in tissue oxidative stress by treatment with either the at 1 r blockade or sod/catalase mimetic. |
| 9958 | REN | renin | renin | 1.0 | investigators have evaluated the efficacy of direct renin inhibition on cardiac oxidative stress and remodeling in the ren2 model of chronic ang ii overexpression using the novel nonpeptide renin inhibitor aliskiren cooper sa et al. unpublished observations . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | investigators have evaluated the efficacy of direct renin inhibition on cardiac oxidative stress and remodeling in the ren2 model of chronic ang ii overexpression using the novel nonpeptide renin inhibitor aliskiren cooper sa et al. unpublished observations . |
| 9958 | REN | renin | renin | 1.0 | the specificity of aliskiren prevents its use in conventional rat models; however the ren2 rat overexpresses murine renin which is recognized by aliskiren 148 158 232 . |
| 9958 | REN | renin | renin | 1.0 | renin is the rate limiting step in the generation of ang ii 148 158 232 ; thus renin inhibition should reduce tissue ang ii levels as well as abrogate any direct renin effects. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | renin is the rate limiting step in the generation of ang ii 148 158 232 ; thus renin inhibition should reduce tissue ang ii levels as well as abrogate any direct renin effects. |
| 9958 | REN | renin | renin | 1.0 | however at 1 r blockade generates a reactive release of renin due to decreased inhibition of renal juxtaglomerular cells which may promote myocardial injury 158 232 . |
| 9958 | REN | renin | renin | 1.0 | thus the reduction of ang ii levels via direct renin inhibition is of potential therapeutic importance as it blocks the raas at its source 148 158 232 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | thus the reduction of ang ii levels via direct renin inhibition is of potential therapeutic importance as it blocks the raas at its source 148 158 232 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | myocardial tissue from untreated heterozygous male ren2 transgenic rats display significantly increased levels of ros generated by increased nadph oxidase activity as evidenced by increased immunostaining for the nadph subunits p47 and rac1 as well as 3 nitrotyrosine. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | translocation of the small gtp binding protein rac1 and p47 to the cell membrane is necessary for the assembly and activation of nadph oxidase which has been directly implicated in ang ii induced cardiac hypertrophy 3 19 50 . 3 nitrotyrosine resulting from ros scavenging of no produces peroxynitrite onoo which binds to protein tyrosine moities to produce stable 3 nitrotyrosine a surro |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | translocation of the small gtp binding protein rac1 and p47 to the cell membrane is necessary for the assembly and activation of nadph oxidase which has been directly implicated in ang ii induced cardiac hypertrophy 3 19 50 . 3 nitrotyrosine resulting from ros scavenging of no produces peroxynitrite onoo which binds to protein tyrosine moit |
| 9958 | REN | renin | renin | 1.0 | direct renin inhibition in ren2 animals significantly reduced levels of myocardial oxidative stress as evidenced by decreased immunostaining for rac1 and nadph subunit p47 as well as 3 nitrotyrosine. |
| 9958 | REN | renin | renin | 1.0 | thus renin blockade effectively attenuated myocardial oxidative stress likely by downregulating nadph oxidase. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | thus renin blockade effectively attenuated myocardial oxidative stress likely by downregulating nadph oxidase. |
| 3327 | ELN | elastin (supravalvular aortic stenosis, Williams-Beuren syndrome) | elastin | 1.0 | additionally interstitial and perivascular fibrosis were evaluated by verhoeff van gieson staining which is specific for elastin collagen connective tissue and nuclei. |
| 9958 | REN | renin | renin | 1.0 | as previously described the ren2 rat exhibited increases in myocardial interstitial and perivascular fibrosis which were abrogated by renin inhibition cooper sa et al. unpublished observations . |
| 9958 | REN | renin | renin | 1.0 | the results of this study complement those of previous studies evaluating the effects of renin inhibition. |
| 9958 | REN | renin | renin | 1.0 | in these studies 135 148 149 218 renin inhibition has been shown to lower blood pressure in spontaneously hypertensive rats double transgenic rats marmosets and hypertensive humans. |
| 9958 | REN | renin | renin | 1.0 | renin inhibition has also been shown to significantly improve cardiac hypertrophy and diastolic and systolic dysfunction as well as reduce albuminuria and kidney inflammation/damage in the double transgeni |
| 6081 | INS | insulin | insulin | 1.0 | however in conditions of insulin resistance glucose metabolism is impaired and the heart is forced to revert to fatty acid and ketone catabolism 146 resulting in structural and other biochemical changes that ultimately lead to left |
| 6081 | INS | insulin | insulin | 1.0 | numerous studies have evaluated myocardial insulin sensitivity in humans 48 71 . |
| 6081 | INS | insulin | insulin | 1.0 | for example our laboratory 64 has used this methodology to measure insulin stimulated myocardial glucose uptake with f dg using the micro pet rodent imaging system and small animal mri fig 5 . |
| 6081 | INS | insulin | insulin | 1.0 | mineralocorticoids cvd and insulin actions |
| 6081 | INS | insulin | insulin | 1.0 | aldosterone exerts a number of maladaptive effects on the vasculature heart and traditional insulin sensitive tissues such as skeletal muscle 4 17 21 26 28 39 49 52 56 59 61 73 76 82 87 90 93 97 99 100 102 108 110 114 116 121 132 134 142 155 157 168 171 177 181 194 196 197 221 228 238 figs 1 3 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | there is accumulating evidence that ang ii and mineralocorticoids have interactive effects on the vasculature fig 1 a and b . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | mineralocorticoids upregulate ang ii receptors in vsmcs 211 and signaling of ang ii is amplified by exposure to mineralocorticoids 210 211 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | both ang ii and aldosterone stimulate vascular growth and remodeling 82 116 121 perhaps mediated through mapk and ros signaling 116 121 155 . |
| 6081 | INS | insulin | insulin | 1.0 | other studies 26 99 have demonstrated that aldosterone may interfere with insulin signaling in various tissues although the effects of mineralocorticoids alone and in conjunction with ang ii on insulin signaling in vascular tissue remain to be elucidated. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | other studies 26 99 have demonstrated that aldosterone may interfere with insulin signaling in various tissues although the effects of mineralocorticoids alone and in conjunction with ang ii on insulin signaling in vascular tissue remain to be elucidated. |
| 2707 | ACE | angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 | angiotensin converting enzyme | 1.0 | additionally mineralocorticoids increase the expression of angiotensin converting enzyme in cardiomyocytes from adult rat primary cardiomyocytes 196 and in cultured rat fetal cardiomyocytes 73 . |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | ang ii | 1.0 | recent data from several laboratories have suggested that mr activation may potentiate the proinflammatory/fibrotic effects of at 1 r signaling by enhancing the cardiac oxidative stress induced by ang ii 90 93 196 238 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | these beneficial effects of mr blockade are mediated in part through the inhibition of nadph oxidase activity 97 100 142 fig 2 . |
| 6081 | INS | insulin | insulin | 1.0 | mineralocorticoids and insulin sensitivity |
| 6081 | INS | insulin | insulin | 1.0 | there are accumulating data from human and animal studies showing that excess mineralocorticoids impair insulin signaling in a number of tissues. |
| 6081 | INS | insulin | insulin | 1.0 | for example an aldosterone excess in patients with primary aldosteronism is related to impaired glucose homeostasis 52 as well as insulin resistance 28 . |
| 6081 | INS | insulin | insulin | 1.0 | several recent publications 99 194 as well as recent data from our laboratory 102 have suggested that these detrimental effects on insulin signaling are mediated by inflammatory/oxidative stress effects of mineralocorticoids. |
| 6081 | INS | insulin | insulin | 1.0 | indeed in the tg mren2 22 rat which manifests insulin resistance 18 in vivo mr antagonism with subpressor doses of spironolactone substantially improve ex vivo insulin stimulated increases in glucose uptake in skeletal muscle a phenomenon that is linked to reductions in nadph oxidase activity and attenuation of ros in soleus muscle tissue 102 . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | vivo mr antagonism with subpressor doses of spironolactone substantially improve ex vivo insulin stimulated increases in glucose uptake in skeletal muscle a phenomenon that is linked to reductions in nadph oxidase activity and attenuation of ros in soleus muscle tissue 102 . |
| 6081 | INS | insulin | insulin | 1.0 | future work will focus on the impact of mr and glucocorticoid receptor antagonism and their impact on insulin and igf 1 signaling in cardiovascular tissue. |
| 7978 | NR3C1 | nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) | glucocorticoid receptor | 1.0 | future work will focus on the impact of mr and glucocorticoid receptor antagonism and their impact on insulin and igf 1 signaling in cardiovascular tissue. |
| 6081 | INS | insulin | insulin | 1.0 | in summary activation of the raas contributes to altered insulin/igf 1 signaling pathways that lead to ros formation endothelial dysfunction and pathological growth and remodeling. |
| 6081 | INS | insulin | insulin | 1.0 | both at 1 r and mr activation contribute to downstream signaling pathways that attenuate insulin signaling mechanisms in the heart vasculature and skeletal muscle that collectively alter the physiological regulation of transcriptional and translational maintenance of cell metabolism. |
| 333 | AGT | angiotensinogen (serpin peptidase inhibitor, clade A, member 8) | angiotensin ii | 1.0 | mineralocorticoids|reactive oxygen species|receptor angiotensin type 1|insulin|angiotensin ii|insulin like growth factor i| |