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Resveratrol Improves Endothelial Function: Role of TNFα and Vascular Oxidative Stress

Objective—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). Methods and Results—We examined endothelial-dependent vasorelaxation to acetylcholine (ACh) in diabetic mice (Leprdb) and normal controls (m Leprdb). Relaxation to ACh was blunted in Leprdb compared with m Leprdb, whereas endothelial-independent vasorelaxation to sodium nitroprusside (SNP) was comparable. Resveratrol improved ACh-induced vasorelaxation in Leprdb without affecting dilator response to SNP. Impaired relaxation to ACh in Leprdb 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 (O2·−) production in Leprdb, whereas both resveratrol and apocynin significantly reduced O2·− signal. Resveratrol increased nitrite/nitrate levels and eNOS (Ser1177) phosphorylation, and attenuated H2O2 production and nitrotyrosine (N-Tyr) content in Leprdb aortas. Furthermore, resveratrol attenuated the mRNA and protein expression of TNFα. Genetic deletion of TNFα in diabetic mice (dbTNF−/dbTNF−) was associated with a reduced NAD(P)H oxidase activity and vascular O2·− 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. Conclusions—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.