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Comparative Study
. 2009 Aug;29(8):1164-71.
doi: 10.1161/ATVBAHA.109.187146. Epub 2009 May 28.

Resveratrol Improves Endothelial Function: Role of TNF{alpha} and Vascular Oxidative Stress

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Free PMC article
Comparative Study

Resveratrol Improves Endothelial Function: Role of TNF{alpha} and Vascular Oxidative Stress

Hanrui Zhang et al. Arterioscler Thromb Vasc Biol. .
Free PMC article

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 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.

Conflict of interest statement

Conflicts of Interest:

None.

Figures

Figure 1
Figure 1
mRNA (A) and protein expression (B) of TNFα (fold change) were significantly higher in Leprdb than in m Leprdb. Resveratrol (RSV) reduced TNFα expression (both mRNA and protein) in Leprdb. n=5 separate experiments. *p<0.05 vs. m Leprdb; #p<0.05 vs. Leprdb.
Figure 2
Figure 2
Representative traces (A) and concentration-response curve (B) showed that endothelial-dependent vasorelaxation to ACh was significantly impaired in aortas of Leprdb. Resveratrol treatment restored impaired vasorelaxation. (C) Endothelial-independent vasorelaxation to SNP was not statistically different among groups. n=7–12 mice. *p<0.05 vs. m Leprdb; #p<0.05 vs. Leprdb.
Figure 3
Figure 3
Genetic deletion of TNFα (dbTNF−/dbTNF−) (A, n=8 mice), apocynin and TEMPOL (C, n=4 mice) partially restored impaired vasorelaxation in Leprdb. TNFα incubation impaired endothelial function in m Leprdb (A, n=6 mice) and abolished the improvement in endothelial function by resveratrol treatment in Leprdb (B, n=6 mice). *p<0.05 vs. m Leprdb; #p<0.05 vs. Leprdb.
Figure 4
Figure 4
(A) Resveratrol, apocynin and genetic deletion of TNFα significantly reduced aortic O2.− production in Leprdb. Incubating aortas of m Leprdb with TNFα increased O2.− production. White arrow indicates the lumen of aorta. (B) and (C), Resveratrol significantly decreased NAD(P)H oxidase activity and gp91phox protein expression in Leprdb. NAD(P)H oxidase activity was lower in dbTNF−/dbTNF− than in Leprdb (B). n=4 separate experiments. *P < 0.05 vs. m Leprdb; #P<0.05 vs. Leprdb.
Figure 5
Figure 5
Aortic nitrite/nitrate level (A) and phosphorylation of eNOS at Ser1177 (B b.) were lower in Leprdb, while total eNOS expression (B a.) was similar among groups. Resveratrol enhanced nitrite/nitrate production and eNOS phosphorylation. eNOS phosphorylation was higher in dbTNF−/dbTNF− than in Leprdb (B b.). n=5 separate experiments. *P<0.05 vs. m Leprdb; #P<0.05 vs. Leprdb.
Figure 6
Figure 6
Aortic N-Tyr expression (A) and serum H2O2 production (B) were higher in Leprdb than in m Leprdb. Resveratrol decreased N-Tyr content and H2O2 levels in Leprdb. n=4 separate experiments. *P<0.05 vs. m Leprdb; #P<0.05 vs. Leprdb.

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