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17891166 ( ) |
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| Title | Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. |
| Abstract | BACKGROUND AND PURPOSE: Diabetes-associated vascular dysfunction contributes to increased cardiovascular risk. We investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve vascular function in diabetic rats. EXPERIMENTAL APPROACH: Male Wistar rats were injected with streptozotocin (50 mg kg(-1), i.v.) to induce insulin-deficient diabetes. Direct effects of sildenafil as well as modification of endothelium-dependent and -independent vasorelaxation were investigated in vitro. The effects of acute and chronic (2 week) treatment in vivo of sildenafil on vascular function were also characterized in isolated aortic segments in organ bath chambers 4 weeks after diabetes induction. KEY RESULTS: Sildenafil induced a concentration-dependent vasorelaxation, which was attenuated by the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine. Acetylcholine-induced endothelium-dependent as well as endothelium-independent relaxation induced by the NO donor, DEA-NONOate, was significantly reduced in aortae from diabetic rats. Incubation with sildenafil in vitro normalized both endothelium-dependent and -independent relaxation in aortae from diabetic rats. Acute as well as chronic in vivo treatment with sildenafil resulted in enhanced endothelium-dependent and -independent vasorelaxation. Superoxide formation was increased in diabetes, associated with enhanced membrane expression of the NAD(P)H oxidase subunit gp91(phox) and Rac, which were both reduced by chronic treatment with sildenafil. CONCLUSIONS AND IMPLICATIONS: We demonstrate that sildenafil treatment rapidly and chronically improves vascular relaxation in diabetic rats. Treatment with sildenafil might provide a similarly beneficial effect in diabetic patients. Julius-Maximilians-Universitat Wurzburg, Wurzburg, Bavaria, Germany. a.schaefer@medizin.uni-wuerzburg.de |
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 |
|---|---|---|---|---|
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | 10 | eNOS | |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | 5 | Rac-1 | |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | 4 | gp91 phox | |
| 8784 | PDE5A | phosphodiesterase 5A, cGMP-specific | 4 | PDE-5 | |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | 3 | nadph oxidase | |
| 132 | ACTB | actin, beta | 2 | beta actin | beta-actin | |
| 6081 | INS | insulin | 2 | insulin | |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | 2 | p47 | |
| 1693 | CD68 | CD68 molecule | 1 | CD68 | |
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | 1 | Rac | |
| 9683 | PTPRU | protein tyrosine phosphatase, receptor type, U | 1 | FMI | |
| 9393 | PRKCA | protein kinase C, alpha | 1 | protein kinase c | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 391 | AKT1 | v-akt murine thymoma viral oncogene homolog 1 | Rac | 1.6 | the NAD(P)H NAD P H oxidase subunit gp91 phox and Rac which were both reduced by chronic treatment with sildenafil |
| 8784 | PDE5A | phosphodiesterase 5A, cGMP-specific | PDE-5 | 0.3 | Similarly PDE-5 inhibition with sildenafil prevents the smoking-induced decrease in flow-mediated vasodilation |
| 9683 | PTPRU | protein tyrosine phosphatase, receptor type, U | FMI | 0.3 | mm rings which were mounted in an organ bath (FMI, FMI Seeheim Germany for isometric force measurements |
| 132 | ACTB | actin, beta | beta-actin | 0.3 | Proteins were electrotransferred onto polyvinylidine difluoride membrane (Immun-Blot Immun-Blot 0.2 beta-actin (4967, 4967 Cell Signaling Technology Frankfurt Germany |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | Endothelial NO synthase (eNOS) eNOS dimer/monomer dimer monomer protein was detected by western blot analysis |
| 1693 | CD68 | CD68 molecule | CD68 | 0.3 | m sections of aorta were stained using primary antibody against CD68 (MCA341R, MCA341R Serotec Disseldorf Germany |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | adenine dinucleotide phosphate (NADPH) NADPH oxidase subunits gp91 phox and p47 phox was significantly increased in aortae from diabetic rats gp91 |
| 7660 | NCF1 | neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1) | p47 | 0.6 | chronic treatment with sildenafil ( Figure 4b whereas the increased p47 phox expression was not changed (data data not shown |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac-1 | 1.6 | Translocation of the small G protein Rac-1 to the plasma membrane activates NADPH oxidase |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac-1 | 1.6 | There was a trend towards increased Rac-1 expression in the aortic membrane in diabetes vs control and |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac-1 | 1.6 | aortic membrane in diabetes vs control and sildenafil significantly reduced Rac-1 expression changes ( Figure 4c |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | throughout the vascular wall endothelium-specific increased superoxide formation by uncoupled eNOS with reduced dimer/monomer dimer monomer ratio has been observed in |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | We found that eNOS dimer/monomer dimer monomer ratio was significantly reduced in the aortae |
| 8784 | PDE5A | phosphodiesterase 5A, cGMP-specific | PDE-5 | 0.3 | study we demonstrate that acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes improves vascular function and reduces |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | C activity as well as increased levels of the endogenous eNOS inhibitor asymmetric dimethylarginine result in enhanced oxidative stress and reduced |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | H oxidase subunit gp91 phox in aortae from diabetic rats eNOS becomes uncoupled under certain circumstances such as high glucose challenge |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | However a major contribution of uncoupled eNOS to superoxide formation in the present experimental condition is unlikely |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac-1 | 1.6 | NAD(P)H NAD P H oxidase subunits and expression changes of Rac-1 favours NAD(P)H NAD P H oxidase as the major source |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | Nevertheless there was a significant shift in eNOS dimer/monomer dimer monomer ratio towards monomer in aortae from diabetic |
| 8784 | PDE5A | phosphodiesterase 5A, cGMP-specific | PDE-5 | 0.3 | of inducing cGMP-dependent vasorelaxation which can be enhanced by the PDE-5 inhibitor sildenafil ( Li et al 2005 |
| 8784 | PDE5A | phosphodiesterase 5A, cGMP-specific | PDE-5 | 0.3 | Thereby PDE-5 inhibition would not only result in the enhancement of the |
| 9801 | RAC1 | ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) | Rac-1 | 1.6 | ( b and membrane expression of the small G protein Rac-1 a NADPH oxidase regulator ( c were assessed by western |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | Uncoupling of eNOS in aortic rings from control rats and diabetic rats (STZ) |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | kg -1 day -1 for 2 weeks was assessed by eNOS dimer/monomer dimer monomer ratio following low temperature SDS-PAGE ( a |
| 7876 | NOS3 | nitric oxide synthase 3 (endothelial cell) | eNOS | 2.2 | aortae was examined by immunohistochemistry for CD68 cells ( b eNOS endothelial NO synthase SDS-PAGE sodium dodecyl sulphate-polyacrylamide gel electrophoresis STZ |
| 6081 | INS | insulin | insulin | 1.0 | experimental approach: male wistar rats were injected with streptozotocin 50 mg kg 1 i.v. to induce insulin deficient diabetes. |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | gp91 phox | 1.0 | superoxide formation was increased in diabetes associated with enhanced membrane expression of the nad p h oxidase subunit gp91 phox and rac which were both reduced by chronic treatment with sildenafil. |
| 6081 | INS | insulin | insulin | 1.0 | impaired endothelial function has been described in very early stages of diabetes mellitus and hyperglycaemia and decreased insulin sensitivity as well as increased oxidative stress have been proposed as possible contributors reviewed by guerci et al 2001 . |
| 132 | ACTB | actin, beta | beta actin | 1.0 | proteins were electrotransferred onto polyvinylidine difluoride membrane immun blot 0.2 beta actin 4967 cell signaling technology frankfurt germany . |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | gp91 phox | 1.0 | expression of the nicotinamide adenine dinucleotide phosphate nadph oxidase subunits gp91 phox and p47 phox was significantly increased in aortae from diabetic rats. gp91 phox expression was significantly reduced by chronic treatment with sildenafil figure 4b whereas the increased p47 phox expression was not changed data not shown . |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | expression of the nicotinamide adenine dinucleotide phosphate nadph oxidase subunits gp91 phox and p47 phox was significantly increased in aortae from diabetic rats. gp91 phox expression was significantly reduced by chronic treatment with sildenafil figure 4b whereas the inc |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | translocation of the small g protein rac 1 to the plasma membrane activates nadph oxidase. |
| 9393 | PRKCA | protein kinase C, alpha | protein kinase c | 1.0 | increased expression of nad p h oxidase subunits enhanced nad p h oxidase and protein kinase c activity as well as increased levels of the endogenous enos inhibitor asymmetric dimethylarginine result in enhanced oxidative stress and reduced no bioavailability in diabetes hink et al 2001 . |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | gp91 phox | 1.0 | we demonstrate that chronic treatment with sildenafil reduces the enhanced superoxide formation and expression of the nad p h oxidase subunit gp91 phox in aortae from diabetic rats. enos becomes uncoupled under certain circumstances such as high glucose challenge to produce superoxide instead of no bauersachs and sch_amp_auml;fer 2005 ; forstermann |
| 2578 | CYBB | cytochrome b-245, beta polypeptide (chronic granulomatous disease) | gp91 phox | 1.0 | expression of the nadph oxidase subunit gp91 phox b and membrane expression of the small g protein rac 1 a nadph oxidase regulator c were assessed by western blot. |
| 14874 | NOX5 | NADPH oxidase, EF-hand calcium binding domain 5 | nadph oxidase | 1.0 | expression of the nadph oxidase subunit gp91 phox b and membrane expression of the small g protein rac 1 a nadph oxidase regulator c were assessed by western blot. |