Published online before print November 6, 2008, doi: 10.1161/CIRCRESAHA.108.181644
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Submitted on June 16, 2008
Revised on October 17, 2008
Accepted on October 29, 2008
P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc
Cuk-Seong Kim ;
From the Cardiovascular Institute (C.-S.K., S.-B.J., A.N., T.A.H., J.D., T.Y., K.I.), University of Pittsburgh Medical Center, Pa; Infection Signaling Network Research Center (B.-H.J.), Department of Physiology, Chungnum National University, Republic of Korea; and Departments of Pharmacology and Chemical Biology (M.P.C., K.I.), University of Pittsburgh, Pa.
* To whom correspondence should be addressed. E-mail: iranik{at}upmc.edu.
P66shc belongs to the shcA family of adaptor proteins. P66shc is structurally and functionally distinct from p52shc and p46shc, the other 2 members of this family. It has a unique N-terminal collagen homology (CH2) domain that is important in governing its activity, and it functions as a protein that promotes oxidative stress within cells and tissues. Little information exists about the mechanisms that govern p66shc expression in the cardiovascular system. We investigated whether both p53 and p66shc play essential roles in impairing endothelium-dependent vasorelaxation triggered by angiotensin II and whether transcriptional upregulation of p66shc by p53 could be an underlying mechanism for this effect. Our findings provide evidence for a novel, evolutionarily conserved mechanism for the transcriptional control of p66shc expression by p53 and make the argument that both p53 and p66shc play essential roles in mediating angiotensin II–induced endothelium-dependent impairment of vasomotor function.
Key words: tumor suppressor p53 • p66shc angiotensin II • endothelial dysfunction