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, Xing Li Wang

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1310-1317
Number of pages8
JournalCirculation research
Volume94
Issue number10
DOIs
StatePublished - May 28 2004

Fingerprint

Ataxia Telangiectasia
Cytomegalovirus
DNA Damage
Wounds and Injuries
Apoptosis
Caspase 3
Endothelial Cells
Caspase 9
Infection
DNA Nucleotidylexotransferase
p53 Genes
Giant Cells
Caspases
Tumor Suppressor Genes
Vascular Diseases
Transcriptional Activation
Cause of Death
Signal Transduction
Atherosclerosis
Up-Regulation

Keywords

  • ATM
  • Apoptosis
  • Cytomegalovirus
  • Endothelium
  • p53

Cite this

Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways. / Shen, Y. H.; Utama, B.; Wang, J.; Raveendran, M.; Senthil, D.; Waldman, W. J.; Belcher, J. D.; Vercellotti, G.; Martin, D.; Mitchelle, B. M.; Wang, Xing Li.

In: Circulation research, Vol. 94, No. 10, 28.05.2004, p. 1310-1317.

Research output: Contribution to journalArticle

Shen, Y. H. ; Utama, B. ; Wang, J. ; Raveendran, M. ; Senthil, D. ; Waldman, W. J. ; Belcher, J. D. ; Vercellotti, G. ; Martin, D. ; Mitchelle, B. M. ; Wang, Xing Li. / Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways. In: Circulation research. 2004 ; Vol. 94, No. 10. pp. 1310-1317.
@article{572760d44ee44cfcbc1a95d43b8280d9,
title = "Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways",
abstract = "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.",
keywords = "ATM, Apoptosis, Cytomegalovirus, Endothelium, p53",
author = "Shen, {Y. H.} and B. Utama and J. Wang and M. Raveendran and D. Senthil and Waldman, {W. J.} and Belcher, {J. D.} and G. Vercellotti and D. Martin and Mitchelle, {B. M.} and Wang, {Xing Li}",
year = "2004",
month = "5",
day = "28",
doi = "10.1161/01.RES.0000129180.13992.43",
language = "English (US)",
volume = "94",
pages = "1310--1317",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways

AU - Shen, Y. H.

AU - Utama, B.

AU - Wang, J.

AU - Raveendran, M.

AU - Senthil, D.

AU - Waldman, W. J.

AU - Belcher, J. D.

AU - Vercellotti, G.

AU - Martin, D.

AU - Mitchelle, B. M.

AU - Wang, Xing Li

PY - 2004/5/28

Y1 - 2004/5/28

N2 - 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.

AB - 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.

KW - ATM

KW - Apoptosis

KW - Cytomegalovirus

KW - Endothelium

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=2642539098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2642539098&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000129180.13992.43

DO - 10.1161/01.RES.0000129180.13992.43

M3 - Article

VL - 94

SP - 1310

EP - 1317

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 10

ER -