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Cardiovascular Research 2006 69(2):502-511; doi:10.1016/j.cardiores.2005.10.007
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Copyright © 2005, European Society of Cardiology

Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10)

Ying H. Shena,*, Lin Zhang, Budi Utamaa, Jian Wanga, Yehua Gana, Xinwen Wanga, Jing Wanga, Li Chena, Greg M. Vercellottib, Joseph S. Cosellia, Jawahar L. Mehtac and Xing Li Wanga,*

aDivision of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Adult Cardiac Services, Texas Heart Institute, St Luke's Episcopal Hospital, Baylor College of Medicine, Houston Texas, United States
bDepartments of Medicine, University of Minneapolis, Minnesota, United States
cDepartment of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States

* Corresponding authors. MS NAB 2010, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, United States. Tel.: +1 713 798 8406; fax: +1 713 798 1705. Email address: hyshen{at}bcm.tmc.edu xlwang{at}bcm.tmc.edu

Objectives: Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV) infection may play a role in the development of this disease. Diminished expression and/or activity of endothelial nitric oxide synthase (eNOS) are an early event in atherogenesis. In the current study, we investigated the effects of HCMV infection on eNOS activation in human aortic endothelial cells (HAECs).

Methods and results: We found that HCMV inhibited eNOS phosphorylation/activation in HAECs. The signaling upstream of eNOS involving Akt and PDK1 were also suppressed by the HCMV infection. Moreover, HCMV infection increased the expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10). Silencing PTEN expression with specific siRNA reversed the inhibitory effects on eNOS activation in HCMV-infected cells indicating the involvement of PTEN in mediating HCMV's inhibitory effects. Next we observed that the activation of p38 MAPK stress signaling pathway mediates HCMV's effects on PTEN up-regulation and eNOS inactivation.

Conclusions: In summary, our findings suggest that inhibition of eNOS leading to endothelial dysfunction may be a basis of the pro-atherogenic effects of HCMV. Importantly, upregulation of PTEN and activation of stress signal p38 MAPK are involved in HCMV's inhibitory effects on eNOS activation.

KEYWORDS Cytomegalovirus; eNOS; Akt; PTEN; p38 MAPK

Time for primary review 22 days


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