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

doi:10.1161/CIRCRESAHA.108.181644

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

Journal article

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Peer reviewed

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 and Kaikobad IRANI

Circulation research, Vol.103(12), pp.1441-1450

2008

DOI: 10.1161/CIRCRESAHA.108.181644

PMID: 18988897

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Abstract

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.

Fundamental and applied biological sciences. Psychology

Biological and medical sciences

Vertebrates: cardiovascular system

Details

Title: Subtitle: P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc
Creators: Cuk-Seong KIM - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Saet-Byel JUNG - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Asma NAQVI - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Timothy A HOFFMAN - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Jeremy DERICCO - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Tohru YAMAMORI - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Marsha P COLE - Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh, Pa, United States
Byeong-Hwa JEON - Infection Signaling Network Research Center Department of Physiology, Chungnum National University, Korea, Republic of
Kaikobad IRANI - Cardiovascular Institute University of Pittsburgh Medical Center, Pa, United States
Resource Type: Journal article
Publication Details: Circulation research, Vol.103(12), pp.1441-1450
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
DOI: 10.1161/CIRCRESAHA.108.181644
PMID: 18988897
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 2008
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047884702771

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