Resveratrol Improves Endothelial Function

<jats:p> <jats:bold> <jats:italic>Objective—</jats:italic> </jats:bold> Oxidative stress plays an important role in type 2 diabetes–related endothelial dysfunction. We hypothesized that resveratrol protects against oxidative stress–induced endothelial dysfunction in aortas of diabetic mice by inhibiting tumor necrosis factor α (TNFα)-induced activation of NAD(P)H oxidase and preserving phosphorylation of endothelial nitric oxide synthase (eNOS). </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> We examined endothelial-dependent vasorelaxation to acetylcholine (ACh) in diabetic mice (Lepr <jats:sup>db</jats:sup> ) and normal controls (m Lepr <jats:sup>db</jats:sup> ). Relaxation to ACh was blunted in Lepr <jats:sup>db</jats:sup> compared with m Lepr <jats:sup>db</jats:sup> , whereas endothelial-independent vasorelaxation to sodium nitroprusside (SNP) was comparable. Resveratrol improved ACh-induced vasorelaxation in Lepr <jats:sup>db</jats:sup> without affecting dilator response to SNP. Impaired relaxation to ACh in Lepr <jats:sup>db</jats:sup> was partially reversed by incubating the vessels with NAD(P)H oxidase inhibitor apocynin and a membrane-permeable superoxide dismutase mimetic TEMPOL. Dihydroethidium (DHE) staining showed an elevated superoxide (O <jats:sub>2</jats:sub> <jats:sup>·−</jats:sup> ) production in Lepr <jats:sup>db</jats:sup> , whereas both resveratrol and apocynin significantly reduced O <jats:sub>2</jats:sub> <jats:sup>·−</jats:sup> signal. Resveratrol increased nitrite/nitrate levels and eNOS (Ser1177) phosphorylation, and attenuated H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> production and nitrotyrosine (N-Tyr) content in Lepr <jats:sup>db</jats:sup> aortas. Furthermore, resveratrol attenuated the mRNA and protein expression of TNFα. Genetic deletion of TNFα in diabetic mice (db <jats:sup>TNF−</jats:sup> /db <jats:sup>TNF−</jats:sup> ) was associated with a reduced NAD(P)H oxidase activity and vascular O <jats:sub>2</jats:sub> <jats:sup>·−</jats:sup> production and an increased eNOS (Ser1177) phosphorylation, suggesting that TNFα plays a pivotal role in aortic dysfunction in diabetes by inducing oxidative stress and reducing NO bioavailability. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> Resveratrol restored endothelial function in type 2 diabetes by inhibiting TNFα-induced activation of NAD(P)H oxidase and preserving eNOS phosphorylation, suggesting the potential for new treatment approaches to promote vascular health in metabolic diseases. </jats:p>