This Article Full Text Full Text (PDF) All Versions of this Article: 29/8/1164    most recent ATVBAHA.109.187146v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zhang, H. Articles by Zhang, C. PubMed PubMed Citation Articles by Zhang, H. Articles by Zhang, C. Related Collections Type 2 diabetes Oxidant stress Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1164.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Resveratrol Improves Endothelial Function

Role of TNF and Vascular Oxidative Stress

Hanrui Zhang; Jing Zhang; Zoltan Ungvari; Cuihua Zhang

From the Department of Internal Medicine, Medical Pharmacology & Physiology and Nutritional Sciences (H.Z., J.Z., C.Z.), Dalton Cardiovascular Research Center, University of Missouri, Columbia; the Department of Physiology (Z.U.), New York Medical College, Valhalla; and the Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine (Z.U.), University of Oklahoma Health Science Center, Oklahoma City.

Correspondence to Cuihua Zhang, MD, PhD, Departments of Internal Medicine, Medical Pharmacology & Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211. E-mail ZhangCu{at}missouri.edu

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 (TNF)-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 (O₂^·–) production in Lepr^db, 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 Lepr^db aortas. Furthermore, resveratrol attenuated the mRNA and protein expression of TNF. Genetic deletion of TNF in diabetic mice (db^TNF–/db^TNF–) was associated with a reduced NAD(P)H oxidase activity and vascular O₂^·– production and an increased eNOS (Ser1177) phosphorylation, suggesting that TNF 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 TNF-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.

We tested whether the naturally occurring polyphenol resveratrol protects against oxidative stress–induced endothelial dysfunction in type 2 diabetes. Our data demonstrate that resveratrol restored endothelial function in type 2 diabetic mice by inhibiting TNF-induced activation of NAD(P)H oxidase and preserving eNOS (Ser1177) phosphorylation.

Key Words: antioxidants • nitric oxide • nitric oxide synthase • superoxide • vasodilation