P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction.
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.
Yamamori
Tohru
T
Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife 620, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, USA.
White
Anthony R
AR
Mattagajasingh
Ilwola
I
Khanday
Firdous A
FA
Haile
Azeb
A
Qi
Bing
B
Jeon
Byeong Hwa
BH
Bugayenko
Artem
A
Kasuno
Kenji
K
Berkowitz
Dan E
DE
Irani
Kaikobad
K
D000109:Acetylcholine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009924:Organ Culture Techniques; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D000090063:Proto-Oncogene Mas; D051381:Rats; D011921:Rats, Inbred WKY; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014665:Vasodilator Agents; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester