title: Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10).
abstract: OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Adult Cardiac Services, Texas Heart Institute, St Luke's Episcopal Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. hyshen@bcm.tmc.edu
authors.forename: Ying H
authors.initials: YH
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Budi
authors.initials: B
authors.lastname: Utama
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yehua
authors.initials: Y
authors.lastname: Gan
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Greg M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Coselli
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D050197:Atherosclerosis / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006801:Humans; D020935:MAP Kinase Signaling System; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D052250:Nitric Oxide Synthase Type III; D064413:3-Phosphoinositide-Dependent Protein Kinases; D051058:Oncogene Protein v-akt; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human