P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: Implications for age-associated vascular dysfunction

Tohru Yamamori, Anthony R. White, Ilwola Mattagajasingh, Firdous A. Khanday, Azeb Haile, Bing Qi, Hwa Jeon Byeong, Artem Bugayenko, Kenji Kasuno, Dan E. Berkowitz, Kaikobad Irani

Research output: Contribution to journalArticlepeer-review

Abstract

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 S1177 (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.

Original languageEnglish (US)
Pages (from-to)992-995
Number of pages4
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number6
DOIs
StatePublished - Dec 2005

Keywords

  • Endothelium
  • Nitric oxide
  • P66shc
  • Ras
  • Vascular tone

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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