title: Role of the phosphatase PTEN in early vascular remodeling.
abstract: BACKGROUND
  The phosphatase PTEN represents an important physiological inhibitor of phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) signalling, however, the functional role of PTEN in the initial phase of angioplasty-induced vascular injury remains elusive. In the present study we sought to determine PTEN's effect on vascular smooth muscle cell (VSMC) apoptosis following acute injury in vivo and in vitro.
  
  
  RESULTS
  Immunohistochemistry indicated a faint basal expression and equal distribution of PTEN in uninjured rat carotid arteries. 12 h following balloon-injury, PTEN expression was strongly increased in apoptotic (TUNEL+) VSMC. In vitro, stimulation with serum or different growth factors or subjecting VSMC to cyclic stretch had no effect on PTEN expression, whereas stimulation with H2O2 robustly increased PTEN expression in a time- and dose-dependent manner. To evaluate the functional role of PTEN expression, human VSMC were transduced with WT-PTEN. Overexpression of PTEN increased the number of apoptotic VSMC (19.8%±4.4 vs. 5.6%±2.3; P<0.001) as determined by TUNEL assay. In contrast, siRNA-mediated knock-down of PTEN attenuated the basal as well as H2O2-induced apoptosis of VSMC. Mechanistically, overexpression of PTEN prevented serum-induced Akt-phosphorylation, whereas siRNA-mediated knock down of PTEN augmented Akt-activation. Moreover, co-transfection of PTEN and a constitutive active Akt mutant prevented PTEN-dependent augmentation of VSMC apoptosis, indicating, that PTEN regulates VSMC apoptosis by inhibition of Akt phosphorylation/activation.
  
  
  CONCLUSIONS
  By interfering with the PI3-K/Akt-dependent survival signalling, the oxidative stress-induced up regulation of PTEN in VSMC of injured arteries augments the sensitivity of VSMC to apoptotic stimuli in the early phase following vascular injury, augmenting the initial injury and cell loss of the injured vessel wall. Thus, these data add to our understanding of PTEN's role during vascular remodelling.
authors.affiliation: Department of Internal Medicine I, Cardiology/Angiology, Giessen University, Giessen, Germany. daniel.sedding@innere.med.uni-giessen.de
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Sedding
authors.forename: Rebecca
authors.initials: R
authors.lastname: Widmer-Teske
authors.forename: Andreas
authors.initials: A
authors.lastname: Mueller
authors.forename: Philipp
authors.initials: P
authors.lastname: Stieger
authors.forename: Jan-Marcus
authors.initials: JM
authors.lastname: Daniel
authors.forename: Dursun
authors.initials: D
authors.lastname: Gündüz
authors.forename: Soni
authors.initials: S
authors.lastname: Pullamsetti
authors.forename: Holger
authors.initials: H
authors.lastname: Nef
authors.forename: Helge
authors.initials: H
authors.lastname: Moellmann
authors.forename: Christian
authors.initials: C
authors.lastname: Troidl
authors.forename: Christian
authors.initials: C
authors.lastname: Hamm
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Braun-Dullaeus
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D017536:Carotid Artery, Common / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase