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(Circulation Research. 2008;103:1441.)
© 2008 American Heart Association, Inc.

Molecular Medicine

P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc

Cuk-Seong Kim, Saet-Byel Jung, Asma Naqvi, Timothy A. Hoffman, Jeremy DeRicco, Tohru Yamamori, Marsha P. Cole, Byeong-Hwa Jeon, Kaikobad Irani

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. Present address for T.Y.: Faculty of Life and Medical Sciences, Doshisha University, Kyoto Japan.

Correspondence to Kaikobad Irani, Cardiovascular Institute, University of Pittsburgh Medical Center, 623S Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail iranik{at}upmc.edu

The transcription factor, p53, and the adaptor protein, p66shc, both play essential roles in promoting oxidative stress in the vascular system. However, the relationship between the two in the context of endothelium-dependent vascular tone is unknown. Here, we report a novel, evolutionarily conserved, p53-mediated transcriptional mechanism that regulates p66shc expression and identify p53 as an important determinant of endothelium-dependent vasomotor function. We provide evidence of a p53 response element in the promoter of p66shc and show that angiotensin II-induced upregulation of p66shc in endothelial cells is dependent on p53. In addition, we demonstrate that downregulation of p66shc expression, as well as inhibition of p53 function in mice, mitigates angiotensin II-induced impairment of endothelium-dependent vasorelaxation, decrease in bioavailable nitric oxide, and hypertension. These findings reveal a novel p53-dependent transcriptional mechanism for the regulation of p66shc expression that is operative in the vascular endothelium and suggest that this mechanism is important in impairing endothelium-dependent vascular relaxation.

Key Words: tumor suppressor p53 • p66shc • angiotensin II • endothelial dysfunction