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(Circulation. 1999;99:1656-1659.)
© 1999 American Heart Association, Inc.

Brief Rapid Communications

Effects of Human Cytomegalovirus Immediate-Early Proteins on p53-mediated Apoptosis in Coronary Artery Smooth Muscle Cells

Koichi Tanaka, MD, PhD; Jian-Ping Zou, MD, PhD; Kazuyo Takeda, MD, PhD; Victor J. Ferrans, MD, PhD; Gordon R. Sandford, PhD; Thomas M. Johnson, PhD; Toren Finkel, MD, PhD; Stephen E. Epstein, MD

From the Cardiology Branch (K. Tanaka, T.M.J., T.F.) and the Pathology Branch (K. Takeda, V.J.F.), National Heart, Lung, and Blood Institute, and the Experimental Immunology Branch (J.P.Z.), National Cancer Institute, National Institutes of Health, Bethesda, Md; the Medical College of Wisconsin, Madison (G.R.S.); and the Cardiovascular Research Foundation, Washington, DC (S.E.E.).

Correspondence to Stephen E. Epstein, MD, Cardiovascular Research Foundation, Washington Hospital Center, 110 Irving St, NW, Suite 4B-1, Washington, DC 20010.

Background—Restenotic and atherosclerotic lesions often contain smooth muscle cells (SMCs), which display high rates of proliferation and apoptosis. Human cytomegalovirus (HCMV) may increase the incidence of restenosis and predispose to atherosclerosis. Although the mechanisms contributing to these processes are unclear, studies demonstrate that one of the immediate-early (IE) gene products of HCMV, IE2-84, binds to and inhibits p53 transcriptional activity. Given the role of p53 in mediating apoptosis, we studied the ability of IE2-84 to inhibit p53-dependent apoptosis in human coronary artery SMCs.

Methods and Results—Apoptosis of SMCs was induced either by use of an adenovirus vector encoding human wild-type p53 protein or by treatment with doxorubicin. HCMV IE1-72 and IE2-84, the major IE proteins of HCMV, were overexpressed separately with adenovirus vectors encoding each protein, and the effects on p53-induced apoptosis were examined by both nick end-labeling (TUNEL) assay and flow cytometry. Expression of IE2-84, but not IE1-72, protected SMCs from p53-mediated apoptosis.

Conclusions—These data indicate that an HCMV IE protein antagonizes p53-mediated apoptosis, suggesting a pathway by which HCMV infection predisposes to SMC accumulation and thereby contributes to restenosis and atherosclerosis.

Key Words: viruses • proteins • apoptosis • restenosis

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