Abstract 1025: Resveratrol Attenuates Oxidative/Nitrative Stress in Diabetes Mellitus by inhibiting TNF alpha induced NF kappa B activation
Diabetes-induced increased oxidative/nitrative stress is postulated to play a significant role in the development of cardiovascular complications. Resveratrol (RSV) is a naturally occurring phytophenol that exhibits cardiovascular protective effects. The present study is designed to elucidate the mechanism by which RSV exerts its protective activities against oxidative/nitrative stress in diabetes mellitus. Diabetic (Leprdb, homozygote) mice were treated with RSV (20mg/kg/d) orally for 4 weeks while the normal control (m Leprdb, heterozygote) received vehicle for RSV. In Leprdb mice, TNF and NFκB protein expression were significantly increased (n=4, p<0.05); gp91phox mRNA and protein expression, NAD(P)H oxidase activities were also markedly enhanced (n=4, p<0.05) vs m Leprdb mice. H2O2 production was greater in serum obtained from Leprdb mice (n=5, p<0.05) and in situ detection of superoxide by DHE staining showed increased intensity of superoxide in Leprdb mice vs m Leprdb mice. Moreover, iNOS and nitrotyrosine (N-tyr) protein expression in Leprdb mice were enhanced (n=4, p<0.05). Administration of RSV to Leprdb mice attenuated oxidative stress by reducing gp91phox mRNA and protein expression (n=4, p<0.05), NAD(P)H oxidase activities (n=4, p<0.05), as well as H2O2 (n=5, p<0.05) and superoxide production. Meanwhile, RSV treatment ameliorated nitrative stress by inhibiting iNOS protein expression (n=4, p<0.05) and consequently blocking overproduction of peroxynitrite evidenced by decreased N-tyr content in Leprdb mice treated with RSV (n=4, p<0.05). Furthermore, TNF and NFκB protein expression were reduced in RSV treated Leprdb mice (n=4, p<0.05). Based on the important role TNF and NFκB play in inducing NAD(P)H and iNOS expression, the anti-oxidative/nitrative activities of RSV may be due to its effects in inhibiting TNF induced NFκB activation. Therefore, our results suggest that RSV protects the endothelium and restores endothelilal function in diabetes mellitus by inhibiting TNF induced NFκB activation and resultant oxidative/nitrative stress.