期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 39, 期 6, 页码 992-995出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2005.09.003
关键词
P66shc; vascular tone; endothelium; nitric oxide; Ras
资金
- NHLBI NIH HHS [P01 HL65608, R01 HL70929] Funding Source: Medline
- NIA NIH HHS [R01 AG21523] Funding Source: Medline
The p66shc adaptor protein mediates age-associated oxidative stress. We examined the role of p66shc in endothelial nitric oxide synthase (eNOS) signaling. Overexpression of p66shc inhibited eNOS-dependent NO production. RNAi-mediated down-regulation of endogenous p66shc led to activation of the proto-oncogene ras, and Akt kinase, with a corresponding increase in phosphorylation of eNOS at S 1177 (S1179 on bovine eNOS). In rat aortic rings, down-regulation of p66shc suppressed the vasoconstrictor response to phenyephrine that was abrogated by treatment with the NOS inhibitor L-NAME, and enhanced vasodilation induced by sub-maximal doses of acetylcholine. These findings highlight a pivotal role for p66shc in inhibiting endothelial NO production, and endothelium-dependent vasorelaxation, that may provide important mechanistic information about endothelial dysfunction seen with aging. (c) 2005 Elsevier Ltd. All rights reserved.
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