on May 28, 2009
Published online before print May 28, 2009, doi: 10.1161/ATVBAHA.109.187146
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Submitted on February 27, 2009
Accepted on May 15, 2009
Resveratrol Improves Endothelial Function. Role of TNF
and Vascular Oxidative Stress
Hanrui 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.
* To whom correspondence should be addressed. 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 (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 TNF. Genetic deletion of TNF 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 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.
Key words: antioxidants • nitric oxide • nitric oxide synthase • superoxide • vasodilation