)| PMID |
17189832 ( ) |
|---|---|
| Title | Antioxidant and antiplatelet effects of rosuvastatin in a hamster model of prediabetes. |
| Abstract | The objectives of this study were to determine the relationships among Type II diabetes (T2DM)-dependent elevations in platelet-derived reactive oxygen species (ROS), platelet-surface protein disulfide isomerase (psPDI) NO-releasing activity, and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin resistance induced by fructose feeding. Platelets from rosuvastatin-treated non-fructose-fed (NFF) and fructose-fed (FF) hamsters were analyzed for aggregability and psPDI-denitrosation activity. Platelets from NFF animals treated with xanthine/xanthine oxidase (X/XO) were assessed for the same parameters and primary aortic endothelial cells (AEC) cultivated with a range of [rosuvastatin] +/- mevalonate were analyzed for ROS production. Platelets from FF hamsters displayed statistically significant enhanced ROS production, diminished psPDI-mediated NO-releasing activity, and hyperaggregability. Suggestively, platelets from NFF animals treated with X/XO displayed characteristics similar to platelets from FF animals. Rosuvastatin elicited a normalizing effect on all parameters measured in platelets from FF animals. Further, ROS production in primary AEC from FF animals could be blunted to that of NFF animals by concentrations of rosuvastatin in the range of those achieved in the bloodstream. Diminished psPDI-dependent NO-releasing activity and increased initial aggregation rates of FF platelets may result from elevated vascular ROS production under conditions of insulin resistance. Normalization of ROS production and platelet aggregation by rosuvastatin indicates its potential use as a vasculoprotective agent. Sunset Avenue, Windsor, Ontario, Canada N9B 3P4. |
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 |
|---|---|---|---|---|
| 7889 | NOX1 | NADPH oxidase 1 | 32 | NOX-derived | NOX-dependent | |
| 12805 | XDH | xanthine dehydrogenase | 10 | xanthine oxidase | |
| 6081 | INS | insulin | 8 | insulin | |
| 399 | ALB | albumin | 6 | albumin | |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 5 | SOD | superoxide dismutase | |
| 8548 | P4HB | procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide | 3 | protein disulfide isomerase | |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | 2 | p22 phox | |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | 1 | p67 phox | |
| 5006 | HMGCR | 3-hydroxy-3-methylglutaryl-Coenzyme A reductase | 1 | 3 hydroxy 3 methylglutaryl coenzyme a reductase | |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | 1 | nitric oxide synthase | |
| 7427 | MT-CYB | mitochondrially encoded cytochrome b | 1 | cytochrome b | |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | 1 | p91 phox | |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | 1 | Rac | |
| 9802 | RAC2 | ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) | 1 | Rac2 | |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | 1 | Rac1 | |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | 1 | p40 | |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | 1 | nadph oxidase | |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | 1 | p47 | |
| 11416 | STN | statin | 1 | statin | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | human Type II diabetics display both elevated NADPH oxidase (NOX)_amp_#x2013;dependent NOX _amp_#x2013 dependent ROS production and a concomitant decrease in platelet-mediated |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Other _amp_#x201c vascular NOX isozymes_amp_#x201d found in endothelial and smooth muscle cells have been |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | In light of the potential role of NOX in diabetes and cardiovascular disease we hypothesized that rosuvastatin would |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | diabetes and cardiovascular disease we hypothesized that rosuvastatin would attenuate NOX activity and perhaps normalize platelet activity by protecting psPDI from |
| 7889 | NOX1 | NADPH oxidase 1 | NOX-dependent | 0.9 | AEC from fructose-fed (FF) FF animals exhibit enhanced production of NOX-dependent ROS |
| 7889 | NOX1 | NADPH oxidase 1 | NOX-derived | 0.9 | Measurement of cellular NOX-derived ROS |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | NOX generates superoxide which is rapidly dismuted to hydrogen peroxide 23 |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | of DPI thus yielding the contribution of ROS derived from NOX |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | Comparison of the results _amp_#xb1 superoxide dismutase (SOD) SOD mimetic show little difference in denitrosation activity suggesting that the |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | NOX activity in 1_amp_#xb0 culture of hamster AEC |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Recent evidence points also to the constitutive expression of NOX in endothelial cells resulting in the generation of low levels |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Elevations in NOX activity have been observed in the pathophysiology of vascular diseases |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | The FF group had 1.6-fold larger NOX activity than NFF |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | of rosuvastatin had no statistically significant effect on the basal NOX activity |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | However elevated NOX activity of endothelial cells derived from FF animals decreased in |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | that restoration of isoprenoid biosynthesis was associated with restoration of NOX function |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | be as follows ROS is produced by enzymes such as NOX or other ROS-producing enzymes and is rapidly converted to H |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD | 0.9 | is rapidly converted to H 2 O 2 by extracellular SOD or by spontaneous dismutation |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | this hypothesis is the recent report indicating that psPDI and NOX are in close spatial contact in the plasma membrane (PM) |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | In the past 5 years several isozymes of NOX have been identified in nonphagocytic cells like platelets 31 smooth |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | In platelets NOX is believed to be plasma-membrane associated 36 however in endothelial |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | to be plasma-membrane associated 36 however in endothelial cells the NOX subunits are largely assembled and found associated with the intracellular |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Vascular NOX isoforms display low (nM) nM constitutive O 2 _amp_#x2212 generation |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | NOX initially identified in neutrophils is a multimeric protein composed of |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | and p91 phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small G-protein Rac1 |
| 7662 | NCF4 | neutrophil cytosolic factor 4, 40kDa | p40 | 0.3 | phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small G-protein Rac1 or Rac2 |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac1 | 0.8 | p47 phox p40 phox p67 phox and the small G-protein Rac1 or Rac2 which translocate to the PM to activate the |
| 9802 | RAC2 | ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) | Rac2 | 0.3 | p40 phox p67 phox and the small G-protein Rac1 or Rac2 which translocate to the PM to activate the catalytic subunits |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 | 0.0 | is a multimeric protein composed of plasma membrane catalytic subunits p22 phox and p91 phox containing cytochrome b 558 cytosolic regulatory |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 0.0 | Assembly of a functional enzyme complex requires association of Rac GTPase and this association appears to be regulated by its |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Biosynthesis of isoprenoids as well as cholesterol requires mevalonate thus NOX activity can be attenuated with HMG-CoA inhibitors 29 and 30 |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | to determine the effects of rosuvastatin on platelet PDI and NOX activities and on in vitro platelet aggregation in the animal |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | initial rates of aggregation could be the result of increased NOX activity i.e. superoxide overproduction observed in platelets of FF hamsters |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | Numerous studies have established links between an elevated pathologic endothelial NOX activity and atherogenesis 1 12 20 and 23 thus the |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | of rosuvastatin on NFF and FF hamster aortic endothelial cell NOX activity ( Fig 7 |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | NFF NOX activity was insensitive to in vitro rosuvastatin exposure |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | In contrast FF animals displayed aortic endothelial NOX activity that was on average 1.8-fold larger than controls and |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | the same level of drug suggests that perhaps a different NOX isozyme is being induced in the animal model of prediabetes |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | It can be postulated that the rosuvastatin-insensitive NFF isoform of NOX possesses a higher affinity for geranylgeranylate or the geranylgeranyl transferase |
| 7889 | NOX1 | NADPH oxidase 1 | NOX | 0.9 | the geranylgeranyl transferase in comparison to the FF isoform of NOX |
| 6081 | INS | insulin | insulin | 1.0 | somerase pspdi no releasing activity and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin resistance induced by fructose feeding. |
| 8548 | P4HB | procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide | protein disulfide isomerase | 1.0 | the objectives of this study were to determine the relationships among type ii diabetes t2dm dependent elevations in platelet derived reactive oxygen species ros platelet surface protein disulfide isomerase pspdi no releasing activity and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | platelets from nff animals treated with xanthine/xanthine oxidase x/xo were assessed for the same parameters and primary aortic endothelial cells aec cultivated with a range of [rosuvastatin] _amp_#xb1; mevalonate were analyzed for ros production. |
| 6081 | INS | insulin | insulin | 1.0 | diminished pspdi dependent no releasing activity and increased initial aggregation rates of ff platelets may result from elevated vascular ros production under conditions of insulin resistance. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | we have recently made the novel and interesting observation that platelets derived from human type ii diabetics display both elevated nadph oxidase nox _amp_#x2013;dependent ros production and a concomitant decrease in platelet mediated liberation of nitric oxide from low molecular weight s nitrosothiols termed denitrosation [7] . |
| 8548 | P4HB | procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide | protein disulfide isomerase | 1.0 | central to both of these events is the enzyme protein disulfide isomerase. |
| 5006 | HMGCR | 3-hydroxy-3-methylglutaryl-Coenzyme A reductase | 3 hydroxy 3 methylglutaryl coenzyme a reductase | 1.0 | inhibitors of 3 hydroxy 3 methylglutaryl coenzyme a reductase hmg coa reductase have shown efficacy in lowering circulating lipid levels and in reducing cardiovascular mortality [14] . |
| 11416 | STN | statin | statin | 1.0 | alternatively statin treatment has been shown to reduce not only coronary events but also ischemic stroke [16] . |
| 6081 | INS | insulin | insulin | 1.0 | olically disturbed upon fructose feeding for 7 days such that it develops hyperinsulinemia and hyperlipidemia in the absence of overt hyperglycemia thus representing a viable model of the prediabetic insulin resistant state [18] . |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | hydrate dextrose apyrase nacl na 2 hpo 4 kh 2 po 4 kcl nahco 3 mgcl 2 _amp_#xb7;6h 2 0 cacl 2 _amp_#xb7;6h 2 0 fructose bsa f12k media endothelial cell growth supplement ecgs porcine heparin xanthine xanthine oxidase thrombin diphenyleneiodonium chloride dpi and mevalonate were purchased from sigma aldrich canada oakville on . |
| 399 | ALB | albumin | albumin | 1.0 | platelets were obtained from prp and washed three times in tyrodes albumin solution by successive rounds of centrifugation for 15_amp_#xa0;min at 900_amp_#xa0; g and 37_amp_#xb0;c. |
| 399 | ALB | albumin | albumin | 1.0 | the first wash was supplemented with 2_amp_#xa0;u/ml heparin and 1_amp_#xa0;u/ml apyrase the second with 1_amp_#xa0;u/ml apyrase and the third wash contained tyrodes albumin solution only without heparin or apyrase. |
| 8548 | P4HB | procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), beta polypeptide | protein disulfide isomerase | 1.0 | platelet surface protein disulfide isomerase denitrosation activity |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | irred cuvette containing 100_amp_#xa0;mm phosphate buffer ph 7.2 with 1_amp_#xa0;mm edta and 100_amp_#xa0;_amp_#x3bc;m gsno in the presence or absence of 50_amp_#xa0;_amp_#x3bc;m of the cell permeant superoxide dismutase mimetic mn iii tmpyp. |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | treatment of nff hamster platelets with xanthine/xanthine oxidase x/xo |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | platelets were isolated as indicated and treated with a range of xanthine concentrations and 1.5_amp_#xa0;mu/ml xanthine oxidase or xanthine alone for 30_amp_#xa0;min. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | importantly platelet denitrosation was measured in the absence and presence of the superoxide dismutase mimetic mn iii tmpyp. |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | comparison of the results _amp_#xb1; superoxide dismutase sod mimetic show little difference in denitrosation activity suggesting that the observed loss in denitrosation activity is not simply due to scavenging of liberated no by elevated levels of superoxi |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | xanthine oxidase is known to generate ros such as superoxide and peroxide through the transfer of electrons from xanthine to molecular oxygen [24] . |
| 6081 | INS | insulin | insulin | 1.0 | the present study was initiated by our observations that both in humans with t2dm and in an animal model of prediabetic insulin resistance elevated platelet production of ros is observed concomitantly with a decrease in pspdi denitrosation activity and enhanced aggregatory potential. |
| 6081 | INS | insulin | insulin | 1.0 | isoforms display low nm constitutive o 2 _amp_#x2212; generation and this basal activity is reported to be potentiated by a variety of stimuli common to type ii diabetes pathology including increased insulin [38] glucose [39] oxidized ldl [40] and hyperlipidemia [41] . |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | p91 phox | 1.0 | nox initially identified in neutrophils is a multimeric protein composed of plasma membrane catalytic subunits p22 phox and p91 phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small g protein rac1 or rac2 which translocate to the pm to activate the catalytic subunits. |
| 2577 | CYBA | cytochrome b-245, alpha polypeptide | p22 phox | 1.0 | nox initially identified in neutrophils is a multimeric protein composed of plasma membrane catalytic subunits p22 phox and p91 phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small g protein rac1 or rac2 which translocate to the pm to activate the catalytic subunits. |
| 7661 | NCF2 | neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2) | p67 phox | 1.0 | ally identified in neutrophils is a multimeric protein composed of plasma membrane catalytic subunits p22 phox and p91 phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small g protein rac1 or rac2 which translocate to the pm to activate the catalytic subunits. |
| 7427 | MT-CYB | mitochondrially encoded cytochrome b | cytochrome b | 1.0 | nox initially identified in neutrophils is a multimeric protein composed of plasma membrane catalytic subunits p22 phox and p91 phox containing cytochrome b 558 cytosolic regulatory subunits p47 phox p40 phox p67 phox and the small g protein rac1 or rac2 which translocate to the pm to activate the catalytic subunits. |
| 6081 | INS | insulin | insulin | 1.0 | previous studies have demonstrated that fructose feeding of hamsters for 2_amp_#x2013;3 weeks induces insulin resistance as confirmed by in vivo euglycemic hyperinsulinemic clamp studies [18] . |
| 6081 | INS | insulin | insulin | 1.0 | fructose feeding is associated with hyperinsulinemia hyperlipidemia but a normoglycemic state suggesting the development of a prediabetic insulin resistant state. |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | to test this we exposed platelets from nff animals to the xanthine/xanthine oxidase superoxide generating system and in support of our hypothesis platelets exposed to a range of xanthine concentrations and 1.5_amp_#xa0;mu/ml xanthine oxidase over 30_amp_#xa0;min 1 inhibited the pspd |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | superoxide generating system and in support of our hypothesis platelets exposed to a range of xanthine concentrations and 1.5_amp_#xa0;mu/ml xanthine oxidase over 30_amp_#xa0;min 1 inhibited the pspdi dependent rsno denitrosation activity by 50% at 25_amp_#xa0;_amp_#x3bc;m xanthine fig 6 a and 2 potentiated the initial rates of thrombin induced aggregatio |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | nitric oxide synthase | 1.0 | diphenyleneiodonium is a flavoprotein inhibitor and will inhibit other enzymes such as nitric oxide synthase which has been shown to produce superoxide in platelets of patients with coexisting hypertension and diabetes [43] . |
| 6081 | INS | insulin | insulin | 1.0 | ion activity in models of prediabetes broadening of the pathological states to which this drug is utilized may be beneficial in preventing secondary atherothrombotic complications associated with non insulin dependent diabetes mellitus. |
| 399 | ALB | albumin | albumin | 1.0 | aggregation of platelets in tyrodes albumin solution was monitored at 630_amp_#xa0;nm after stimulation with 0.5_amp_#xa0;u/ml thrombin over a 10 min time period. |
| 399 | ALB | albumin | albumin | 1.0 | aggregation of platelets in tyrodes albumin solution was monitored at 630_amp_#xa0;nm after stimulation with 0.5_amp_#xa0;u/ml thrombin in the presence or absence of 12.5_amp_#xa0;_amp_#x3bc;m gsno over a 10 min time period. |
| 399 | ALB | albumin | albumin | 1.0 | similarly platelets isolated from nff fed animals were suspended in tyrodes albumin solution and exposed to a transient 30_amp_#xa0;min flux of superoxide generated from 0 to 10_amp_#xa0;_amp_#x3bc;m xanthine and 1.5_amp_#xa0;mu/ml xanthine oxidase verified to be complete within the |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | m nff fed animals were suspended in tyrodes albumin solution and exposed to a transient 30_amp_#xa0;min flux of superoxide generated from 0 to 10_amp_#xa0;_amp_#x3bc;m xanthine and 1.5_amp_#xa0;mu/ml xanthine oxidase verified to be complete within the allotted time. |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | platelets were obtained from nff hamsters by centrifugation and then exposed to a transient 30_amp_#xa0;min flux of superoxide generated from 25_amp_#xa0;_amp_#x3bc;m xanthine and 1.5_amp_#xa0;mu/ml xanthine oxidase verified to be complete within the allotted time. |
| 12805 | XDH | xanthine dehydrogenase | xanthine oxidase | 1.0 | platelets were obtained from nff hamsters by centrifugation and then exposed to a transient 30_amp_#xa0;min flux of superoxide generated from 25_amp_#xa0;_amp_#x3bc;m xanthine and 1.5_amp_#xa0;mu/ml xanthine oxidase. |
| 399 | ALB | albumin | albumin | 1.0 | platelets 10 8 were suspended in tyrodes albumin buffer in triplicate and aggregation was initiated by the addition of 0.5_amp_#xa0;u/ml thrombin. |