Resveratrol, a phytoalexin, has recently gained attention for protective effects against metabolic and cardiac diseases. The beneficial effects of resveratrol have been linked to sirtuin-1 (SIRT-1) activation. However, little is known about the effect of resveratrol in cardiac complications associated with diabetes. Here, we have demonstrated that resveratrol ameliorates cardiac hypertrophy, electrocardiographic abnormalities and oxidative stress in the fructose-fed diabetic rat heart. Mechanistic studies revealed that fructose feeding to Sprague-Dawley rats over a period of 8 weeks leads to cardiac hypertrophy and increased oxidative stress through increased activity of NADPH oxidase (NOX) and reactive oxygen species production. We found increased activity of nuclear factor kappa B (NFkB) p-65 along with decreased SIRT-1 activity in the diabetic heart. Resveratrol activates SIRT-1, which deacetylates NFkB-p65 at lysine 310 and histone 3 (H3) at lysine 9 position. SIRT1 activation leads to decreased binding of NFkB-p65 to DNA and attenuated cardiac hypertrophy and oxidative stress through reduced transcription of NADPH oxidase subunits. In vitro analysis also revealed that SIRT-1 activation by resveratrol is associated with decreased NFkB-p65 activity and NOX transcription. Similarly, knockdown or inhibition of SIRT1 in H9C2 cells increased acetylation of NFkB-p65 K310 and H3K9. Overall, our data demonstrated that SIRT-1 activation by resveratrol leads to deacetylation of both NFkB-p65 and H3, thereby attenuating cardiac oxidative stress and complications in diabetes.
Keywords: Acetylation; Diabetic cardiomyopathy; Histone; NFkB; Oxidative stress; Resveratrol; SIRT-1.
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