Resveratrol Improves Endothelial Function

Abstract

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 (Lepr db ) and normal controls (m Lepr db ). Relaxation to ACh was blunted in Lepr db compared with m Lepr db , whereas endothelial-independent vasorelaxation to sodium nitroprusside (SNP) was comparable. Resveratrol improved ACh-induced vasorelaxation in Lepr db without affecting dilator response to SNP. Impaired relaxation to ACh in Lepr db 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 2 ·− ) production in Lepr db , whereas both resveratrol and apocynin significantly reduced O 2 ·− signal. Resveratrol increased nitrite/nitrate levels and eNOS (Ser1177) phosphorylation, and attenuated H 2 O 2 production and nitrotyrosine (N-Tyr) content in Lepr db aortas. Furthermore, resveratrol attenuated the mRNA and protein expression of TNFα. Genetic deletion of TNFα in diabetic mice (db TNF− /db TNF− ) was associated with a reduced NAD(P)H oxidase activity and vascular O 2 ·− 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.