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

doi:10.1016/j.cardiores.2005.10.007

Cardiovascular Research 2006 69(2):502-511; doi:10.1016/j.cardiores.2005.10.007

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

Ying H. Shen^a^,*, Lin Zhang, Budi Utama^a, Jian Wang^a, Yehua Gan^a, Xinwen Wang^a, Jing Wang^a, Li Chen^a, Greg M. Vercellotti^b, Joseph S. Coselli^a, Jawahar L. Mehta^c and Xing Li Wang^a^,*

^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 inthe United States, and human cytomegalovirus (HCMV) infectionmay play a role in the development of this disease. Diminishedexpression 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 activationin human aortic endothelial cells (HAECs).

Methods and results: We found that HCMV inhibited eNOS phosphorylation/activationin HAECs. The signaling upstream of eNOS involving Akt and PDK1were also suppressed by the HCMV infection. Moreover, HCMV infectionincreased the expression of PTEN (phosphatase and tensin homologdeleted on chromosome 10). Silencing PTEN expression with specificsiRNA reversed the inhibitory effects on eNOS activation inHCMV-infected cells indicating the involvement of PTEN in mediatingHCMV's inhibitory effects. Next we observed that the activationof p38 MAPK stress signaling pathway mediates HCMV's effectson PTEN up-regulation and eNOS inactivation.

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

KEYWORDS Cytomegalovirus; eNOS; Akt; PTEN; p38 MAPK

Time for primary review 22 days

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