| First Author | Zhang H | Year | 2009 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 29 |
| Issue | 8 | Pages | 1164-71 |
| PubMed ID | 19478208 | Mgi Jnum | J:167814 |
| Mgi Id | MGI:4880633 | Doi | 10.1161/ATVBAHA.109.187146 |
| Citation | Zhang H, et al. (2009) Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. Arterioscler Thromb Vasc Biol 29(8):1164-71 |
| abstractText | 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. |
