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Peroxynitrite mediates diabetes-induced endothelial dysfunction: possible role of Rho kinase activation.

El-Remessy AB, Tawfik HE, Matragoon S, Pillai B, Caldwell RB, Caldwell RW - Exp Diabetes Res (2010)

Bottom Line: Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls.Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression.Treatment of diabetic animals with FeTTPS blocked these effects.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, The University of Georgia, 1120 15th Street, HM-1200, Augusta, GA 30912, USA. aelremessy@mcg.edu

ABSTRACT
Endothelial dysfunction is characterized by reduced bioavailability of NO due to its inactivation to form peroxynitrite or reduced expression of eNOS. Here, we examine the causal role of peroxynitrite in mediating diabetes-induced endothelial dysfunction. Diabetes was induced by STZ-injection, and rats received the peroxynitrite decomposition catalyst (FeTTPs, 15 mg/Kg/day) for 4 weeks. Vasorelaxation to acetylcholine, oxidative-stress markers, RhoA activity, and eNOS expression were determined. Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls. Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression. Treatment of diabetic animals with FeTTPS blocked these effects. Studies in aortic endothelial cells show that high glucose or peroxynitrite increases the active RhoA kinase levels and decreases eNOS expression and NO levels, which were reversed with blocking peroxynitrite or Rho kinase. Together, peroxynitrite can suppress eNOS expression via activation of RhoA and hence cause vascular dysfunction.

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FeTPPs restored nitric oxide production and eNOS expression in diabetic rat vessels. (a) Diabetes significantly reduced NO formation in rat aortic homogenate as measured by NO analyzer. Cotreatment of diabetic animals with FeTPPs restored NO back to normal levels (n = 6 in each group). Values are expressed as means ± SEM, *P < .05 versus control. (b) Real-time PCR of eNOS expression from aortic endothelial homogenate showed that diabetes significantly decreased eNOS expression (~50%) of control level, and FeTPPs restored eNOS expression to 87% of basal level (n = 5 in each group). Values are expressed as means ± SEM, *P < .05 versus control.
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fig3: FeTPPs restored nitric oxide production and eNOS expression in diabetic rat vessels. (a) Diabetes significantly reduced NO formation in rat aortic homogenate as measured by NO analyzer. Cotreatment of diabetic animals with FeTPPs restored NO back to normal levels (n = 6 in each group). Values are expressed as means ± SEM, *P < .05 versus control. (b) Real-time PCR of eNOS expression from aortic endothelial homogenate showed that diabetes significantly decreased eNOS expression (~50%) of control level, and FeTPPs restored eNOS expression to 87% of basal level (n = 5 in each group). Values are expressed as means ± SEM, *P < .05 versus control.

Mentions: In order to test whether the increased oxidative stress in diabetic rats reduces NO availability, we determined NO formation using a NO analyzer. As shown in Figure 3(a), diabetes significantly reduced NO production by 50% below control level. Cotreatment of diabetic animals with FeTPPs (15 mg/Kg/day) prevented the reduction in NO production to control levels.


Peroxynitrite mediates diabetes-induced endothelial dysfunction: possible role of Rho kinase activation.

El-Remessy AB, Tawfik HE, Matragoon S, Pillai B, Caldwell RB, Caldwell RW - Exp Diabetes Res (2010)

FeTPPs restored nitric oxide production and eNOS expression in diabetic rat vessels. (a) Diabetes significantly reduced NO formation in rat aortic homogenate as measured by NO analyzer. Cotreatment of diabetic animals with FeTPPs restored NO back to normal levels (n = 6 in each group). Values are expressed as means ± SEM, *P < .05 versus control. (b) Real-time PCR of eNOS expression from aortic endothelial homogenate showed that diabetes significantly decreased eNOS expression (~50%) of control level, and FeTPPs restored eNOS expression to 87% of basal level (n = 5 in each group). Values are expressed as means ± SEM, *P < .05 versus control.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967829&req=5

fig3: FeTPPs restored nitric oxide production and eNOS expression in diabetic rat vessels. (a) Diabetes significantly reduced NO formation in rat aortic homogenate as measured by NO analyzer. Cotreatment of diabetic animals with FeTPPs restored NO back to normal levels (n = 6 in each group). Values are expressed as means ± SEM, *P < .05 versus control. (b) Real-time PCR of eNOS expression from aortic endothelial homogenate showed that diabetes significantly decreased eNOS expression (~50%) of control level, and FeTPPs restored eNOS expression to 87% of basal level (n = 5 in each group). Values are expressed as means ± SEM, *P < .05 versus control.
Mentions: In order to test whether the increased oxidative stress in diabetic rats reduces NO availability, we determined NO formation using a NO analyzer. As shown in Figure 3(a), diabetes significantly reduced NO production by 50% below control level. Cotreatment of diabetic animals with FeTPPs (15 mg/Kg/day) prevented the reduction in NO production to control levels.

Bottom Line: Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls.Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression.Treatment of diabetic animals with FeTTPS blocked these effects.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, The University of Georgia, 1120 15th Street, HM-1200, Augusta, GA 30912, USA. aelremessy@mcg.edu

ABSTRACT
Endothelial dysfunction is characterized by reduced bioavailability of NO due to its inactivation to form peroxynitrite or reduced expression of eNOS. Here, we examine the causal role of peroxynitrite in mediating diabetes-induced endothelial dysfunction. Diabetes was induced by STZ-injection, and rats received the peroxynitrite decomposition catalyst (FeTTPs, 15 mg/Kg/day) for 4 weeks. Vasorelaxation to acetylcholine, oxidative-stress markers, RhoA activity, and eNOS expression were determined. Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls. Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression. Treatment of diabetic animals with FeTTPS blocked these effects. Studies in aortic endothelial cells show that high glucose or peroxynitrite increases the active RhoA kinase levels and decreases eNOS expression and NO levels, which were reversed with blocking peroxynitrite or Rho kinase. Together, peroxynitrite can suppress eNOS expression via activation of RhoA and hence cause vascular dysfunction.

Show MeSH
Related in: MedlinePlus