Resveratrol is a natural phytophenol that exhibits cardioprotective effects. This study is designed to elucidate the mechanisms by which resveratrol protects against diabetes-induced cardiac dysfunction. Normal controls (m Leprdb) and type 2 diabetic mice (Leprdb) were treated with resveratrol orally for 4 weeks. In vivo magnetic resonance imaging (MRI) showed that resveratrol improved cardiac function by increasing left ventricular diastolic peak filling rate (PFR) in Leprdb. This protective role is partially explained by resveratrol's effects in improving nitric oxide (NO) production and inhibiting oxidative/nitrative stress in cardiac tissue. Resveratrol increased NO production by enhancing endothelial nitric oxide synthase (eNOS) expression, and reduced O2⋅- production by inhibiting NAD(P)H oxidase activity, gp91phox mRNA and protein expression. Increased nitrotyrosine (N-Tyr) protein expression in Leprdb was prevented by inducible NOS (iNOS) inhibitor, 1400W. Resveratrol reduced both N-Tyr and iNOS expression in Leprdb. Furthermore, tumor necrosis factor-alpha (TNFα) mRNA and protein expression, as well as nuclear factor-kappaB (NFκB) activation were reduced in resveratrol-treated Leprdb. Both Leprdb mice null for TNFα (dbTNF-/dbTNF-) and Leprdb treated with NFκB inhibitor MG132 showed decreased NAD(P)H oxidase activity and iNOS expression, as well as elevated eNOS expression, while m Leprdb treated with TNFα showed opposite effects. Thus, resveratrol protects against cardiac dysfunction by inhibiting oxidative/nitrative stress and improving NO availability. This improvement is due to the role of resveratrol in inhibiting TNFα-induced NFκB activation, therefore subsequently inhibiting the expression and activation of NAD(P)H oxidase and iNOS, as well as increasing eNOS expression in type 2 diabetes.
- Cardiac Diabetic Complication
- Antioxidants and Free Radicals
- Nitric Oxide
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology