This Article Full Text Full Text (PDF) All Versions of this Article: 94/10/1310    most recent 01.RES.0000129180.13992.43v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, Y.H. Articles by Wang, X.L. Search for Related Content PubMed PubMed Citation Articles by Shen, Y.H. Articles by Wang, X.L. Related Collections Apoptosis Risk Factors Cell signalling/signal transduction Endothelium/vascular type/nitric oxide

(Circulation Research. 2004;94:1310.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Human Cytomegalovirus Causes Endothelial Injury Through the Ataxia Telangiectasia Mutant and p53 DNA Damage Signaling Pathways

Y.H. Shen, B. Utama, J. Wang, M. Raveendran, D. Senthil, W.J. Waldman, J.D. Belcher, G. Vercellotti, D. Martin, B.M. Mitchelle, X.L. Wang

From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (Y.H.S., B.U., J.W., M.R., D.S., X.L.W.), Departments of Ophthalmology and Molecular Virology and Microbiology (B.M.M.), Baylor College of Medicine, Houston, Tex; Department of Pathology (W.J.W.), Ohio State University, College of Medicine and Public Health, Columbus; Department of Medicine (D.B., G.V.), University of Minnesota Medical School, Minneapolis; and Department of Virology (D.M.), Southwest Foundation for Biomedical Research, San Antonio, Tex.

Correspondence to Dr Xing Li Wang, MS NAB 2010, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail xlwang{at}bcm.tmc.edu

Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV), a member of the herpes virus family, may play a role in the development of the disease. We previously showed that HCMV regulated endothelial apoptosis. In this study, we investigated the induction of apoptosis and signal transduction pathways regulating this process in HCMV-infected endothelial cells. As observed previously, HCMV induced a typical cytopathic effect in human aortic endothelial cells (HAECs), ie, the formation of single nucleated or multinucleated giant cells. Although infected HAECs were resistant to apoptosis at earlier stages of infection, they became apoptotic with prolonged infection as demonstrated by positive staining using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). This apoptotic process was mediated by the caspase-dependent mitochondrial apoptotic pathway as indicated by increased expression and cleavage of caspases 3 and 9 as well as increased expressions of pro-apoptotic molecules Bax and Bak. Blocking caspases 3 or 9 significantly inhibited the HCMV-induced apoptosis. Further exploration of the upstream pathway demonstrated upregulation of the tumor suppressor p53 gene and activation of the ataxia telangiectasia mutant (ATM) pathway in the infected cells. Blocking p53 inhibited HCMV-stimulated Bax and Bak expression as well as caspase-3 activation and blocking the ATM pathway inhibited HCMV-stimulated p53 activation. Although early infection may render cells antiapoptotic, prolonged infection, however, induced endothelial apoptosis through ATM and p53-dependent activation of the mitochondrial death pathway. This proapoptotic effect may be relevant to endothelial dysfunction and HCMV-associated vascular diseases.

Key Words: cytomegalovirus • endothelium • ATM • p53 • apoptosis

This article has been cited by other articles:

				Z. Chen, E. Knutson, S. Wang, L. A. Martinez, and T. Albrecht Stabilization of p53 in Human Cytomegalovirus-initiated Cells Is Associated with Sequestration of HDM2 and Decreased p53 Ubiquitination J. Biol. Chem., October 5, 2007; 282(40): 29284 - 29295. [Abstract] [Full Text] [PDF]

				B. Utama, Y. H. Shen, B. M. Mitchell, I. T. Makagiansar, Y. Gan, R. Muthuswamy, S. Duraisamy, D. Martin, X. Wang, M.-X. Zhang, et al. Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells J. Cell Sci., June 15, 2006; 119(12): 2457 - 2467. [Abstract] [Full Text] [PDF]

				X. Liang, M. T. Pickering, N.-H. Cho, H. Chang, M. R. Volkert, T. F. Kowalik, and J. U. Jung Deregulation of DNA Damage Signal Transduction by Herpesvirus Latency-Associated M2. J. Virol., June 1, 2006; 80(12): 5862 - 5874. [Abstract] [Full Text] [PDF]

				M. Gaspar and T. Shenk Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins PNAS, February 21, 2006; 103(8): 2821 - 2826. [Abstract] [Full Text] [PDF]

				Y. H. Shen, L. Zhang, B. Utama, J. Wang, Y. Gan, X. Wang, J. Wang, L. Chen, G. M. Vercellotti, J. S. Coselli, et al. Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10) Cardiovasc Res, February 1, 2006; 69(2): 502 - 511. [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]

				M. Patrone, M. Secchi, L. Fiorina, M. Ierardi, G. Milanesi, and A. Gallina Human Cytomegalovirus UL130 Protein Promotes Endothelial Cell Infection through a Producer Cell Modification of the Virion J. Virol., July 1, 2005; 79(13): 8361 - 8373. [Abstract] [Full Text] [PDF]

				S.-J. Lee, K.-M. Kim, S. Namkoong, C.-K. Kim, Y.-C. Kang, H. Lee, K.-S. Ha, J.-A Han, H.-T. Chung, Y.-G. Kwon, et al. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine J. Biol. Chem., February 18, 2005; 280(7): 5781 - 5788. [Abstract] [Full Text] [PDF]

				Y.-J. Song and M. F. Stinski Inhibition of Cell Division by the Human Cytomegalovirus IE86 Protein: Role of the p53 Pathway or Cyclin-Dependent Kinase 1/Cyclin B1 J. Virol., February 15, 2005; 79(4): 2597 - 2603. [Abstract] [Full Text] [PDF]