Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress

Arterioscler Thromb Vasc Biol. 2009 Aug;29(8):1164-71. doi: 10.1161/ATVBAHA.109.187146. Epub 2009 May 28.


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).

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 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / physiopathology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology*
  • Female
  • Gene Expression Regulation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidases / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics*
  • Resveratrol
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stilbenes / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics*
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology


  • RNA, Messenger
  • Stilbenes
  • Tumor Necrosis Factor-alpha
  • Vasodilator Agents
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • NADPH Oxidases
  • Resveratrol