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(Circulation. 2003;108:464.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Paradoxical Upregulation of Tumor Suppressor Protein p53 in Serum-Stimulated Vascular Smooth Muscle Cells

A Novel Negative-Feedback Regulatory Mechanism

Zakar H. Mnjoyan, PhD; Ranjan Dutta, PhD; Di Zhang, MS; Ba-Bie Teng, PhD; Ken Fujise, MD

From the Research Center for Cardiovascular Diseases (Z.H.M., D.Z., K.F.) and the Research Center for Human Genetics (R.D., B.-B.T.), Institute of Molecular Medicine for the Prevention of Human Diseases, and the Division of Cardiology, Department of Internal Medicine (K.F.), The University of Texas–Houston Health Science Center.

Correspondence to Ken Fujise, MD, 6431 Fannin St, Suite 1.246, Houston, TX 77030. E-mail kenichi.fujise{at}uth.tmc.edu

Received December 19, 2002; revision received March 20, 2003; accepted April 14, 2003.

Background— The proliferative response of vascular smooth muscle cells (VSMCs) to various growth stimuli is critical for atherosclerosis and postangioplasty restenosis. Although tumor suppressor protein p53 plays a critical role in the elimination of cancerous cells, recent genetic studies have indicated that it also protects against atherosclerosis and restenosis.

Methods and Results— We examined the levels of p53 protein in normal VSMCs before and after serum stimulation. The p53 protein levels increased robustly on stimulation. Upregulated p53 protein was capable of binding to the p53 consensus sequence, as shown by electrophoretic mobility shift assay. In addition, p53 upregulation was associated with increases in the transcript and protein levels of p21^WAF1/CIP1 and Bax, as shown by real-time reverse transcriptase–polymerase chain reaction and Western blot analysis, respectively. Furthermore, the upregulation of p21^WAF1/CIP1 and Bax was followed by cell-cycle arrest and apoptosis induction, as shown by 5-bromo-2'-dUTP incorporation assay and terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling staining, respectively. Finally, double-staining analyses showed that the majority of p53-expressing cells also expressed p21^WAF1/CIP1 and Bax proteins.

Conclusions— p53 protein expression in quiescent VSMCs is paradoxically increased by application of a growth stimulus. Through the mediation of p21^WAF1/CIP1 and Bax, the induced p53 protein negatively regulates the growth of dividing VSMCs, thereby minimizing the inappropriate accumulation of VSMCs. Therefore, p53 may be a negative regulator of VSMC growth.

Key Words: angioplasty • restenosis • atherosclerosis • growth substances • apoptosis

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