Resveratrol improves endothelial function: role of TNF{alpha} 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 alpha (TNFalpha)-induced activation of NAD(P)H oxidase and preserving phosphorylation of endothelial nitric oxide synthase (eNOS).


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 TNFalpha. Genetic deletion of TNFalpha 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 TNFalpha 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 TNFalpha-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.
Zhang
Hanrui
H
Departments of Internal Medicine, Medical Pharmacology & Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
Zhang
Jing
J
Ungvari
Zoltan
Z
Zhang
Cuihua
C
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D012333:RNA, Messenger; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000077185:Resveratrol