(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
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
This article has been cited by other articles:
 |
|
 |
|
  E.-S. Hwang, Z. Zhang, H. Cai, D. Y. Huang, S.-M. Huong, C.-Y. Cha, and E.-S. Huang Human Cytomegalovirus IE1-72 Protein Interacts with p53 and Inhibits p53-Dependent Transactivation by a Mechanism Different from That of IE2-86 Protein J. Virol., December 1, 2009; 83(23): 12388 - 12398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Epstein, J. Zhu, A. H. Najafi, and M. S. Burnett Insights Into the Role of Infection in Atherogenesis and in Plaque Rupture Circulation, June 23, 2009; 119(24): 3133 - 3141. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Koh, K. Lee, J.-H. Ahn, and S. Kim Human cytomegalovirus infection downregulates the expression of glial fibrillary acidic protein in human glioblastoma U373MG cells: identification of viral genes and protein domains involved J. Gen. Virol., April 1, 2009; 90(4): 954 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Sanders, C. L. Clark, C. S. Morello, and D. H. Spector Development of Cell Lines That Provide Tightly Controlled Temporal Translation of the Human Cytomegalovirus IE2 Proteins for Complementation and Functional Analyses of Growth-Impaired and Nonviable IE2 Mutant Viruses J. Virol., July 15, 2008; 82(14): 7059 - 7077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shlapobersky, R. Sanders, C. Clark, and D. H. Spector Repression of HMGA2 Gene Expression by Human Cytomegalovirus Involves the IE2 86-Kilodalton Protein and Is Necessary for Efficient Viral Replication and Inhibition of Cyclin A Transcription. J. Virol., October 1, 2006; 80(20): 9951 - 9961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Castillo, F. M. Frame, H. A. Rogoff, M. T. Pickering, A. D. Yurochko, and T. F. Kowalik Human Cytomegalovirus IE1-72 Activates Ataxia Telangiectasia Mutated Kinase and a p53/p21-Mediated Growth Arrest Response J. Virol., September 1, 2005; 79(17): 11467 - 11475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Q. Nhan, W. C. Liles, and S. M. Schwartz Role of Caspases in Death and Survival of the Plaque Macrophage Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 895 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sata, K. Tanaka, N. Ishizaka, Y. Hirata, and R. Nagai Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1548 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ducloux, B. Challier, P. Saas, P. Tiberghien, and J.-M. Chalopin CD4 Cell Lymphopenia and Atherosclerosis in Renal Transplant Recipients J. Am. Soc. Nephrol., March 1, 2003; 14(3): 767 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. McCormick, V. L. Smith, D. Chow, and E. S. Mocarski Disruption of Mitochondrial Networks by the Human Cytomegalovirus UL37 Gene Product Viral Mitochondrion-Localized Inhibitor of Apoptosis J. Virol., December 6, 2002; 77(1): 631 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mauser, S.'i. Saito, E. Appella, C. W. Anderson, W. T. Seaman, and S. Kenney The Epstein-Barr Virus Immediate-Early Protein BZLF1 Regulates p53 Function through Multiple Mechanisms J. Virol., November 13, 2002; 76(24): 12503 - 12512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Suzuki, B. Murtuza, N. Suzuki, M. Khan, Y. Kaneda, and M. H. Yacoub Human Cytomegalovirus Immediate-Early Protein IE2-86, but not IE1-72, Causes Graft Coronary Arteriopathy in the Transplanted Rat Heart Circulation, September 24, 2002; 106(12_suppl_1): I-158 - I-162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Geng and P. Libby Progression of Atheroma: A Struggle Between Death and Procreation Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1370 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Scott, M. O'Sullivan, S. Hafizi, L. M. Shapiro, and M. R. Bennett Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis Circ. Res., March 8, 2002; 90(4): 398 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. P. Agema, J. W. Jukema, S. N. Pimstone, and J. J. P. Kastelein Genetic aspects of restenosis after percutaneous coronary interventions;towards more tailored therapy Eur. Heart J., November 2, 2001; 22(22): 2058 - 2074. [PDF]
|
|
|
|
|
|
F.-J. Neumann, A. Kastrati, T. Miethke, J. Mehilli, G. Pogatsa-Murray, W. Koch, M. Seyfarth, and A. Schomig Previous Cytomegalovirus Infection and Restenosis After Coronary Stent Placement Circulation, September 4, 2001; 104(10): 1135 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Guetta, E. M Scarpati, and P. E DiCorleto Effect of cytomegalovirus immediate early gene products on endothelial cell gene activity Cardiovasc Res, June 1, 2001; 50(3): 538 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Castillo, A. D. Yurochko, and T. F. Kowalik Role of Human Cytomegalovirus Immediate-Early Proteins in Cell Growth Control J. Virol., September 1, 2000; 74(17): 8028 - 8037. [Abstract] [Full Text]
|
|
|
|
|
|
S. E. Epstein, J. Zhu, M. S. Burnett, Y. F. Zhou, G. Vercellotti, and D. Hajjar Infection and Atherosclerosis : Potential Roles of Pathogen Burden and Molecular Mimicry Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1417 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Walsh and J. M. Isner Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall Cardiovasc Res, February 1, 2000; 45(3): 756 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Epstein, Y. F. Zhou, and J. Zhu Infection and Atherosclerosis : Emerging Mechanistic Paradigms Circulation, July 27, 1999; 100 (4): e20 - e28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Scott, M. O'Sullivan, S. Hafizi, L. M. Shapiro, and M. R. Bennett Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53: Implications for Brachytherapy and Drug Treatment for Restenosis Circ. Res., March 8, 2002; 90(4): 398 - 404. [Abstract] [Full Text] [PDF]
|
|