Published online before print April 22, 2004, doi: 10.1161/01.RES.0000129180.13992.43
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Submitted on January 6, 2004
Revised on April 7, 2004
Accepted on April 12, 2004
Human Cytomegalovirus Causes Endothelial Injury Through the Ataxia Telangiectasia Mutant and p53 DNA Damage Signaling Pathways
Y. H. Shen ;
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; Department of Virology (D.M.), Southwest Foundation for Biomedical Research, San Antonio, Tex.
* To whom correspondence should be addressed. 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
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