title: Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms.
abstract: The aims of the present study were to examine signaling mechanisms for PDGF-induced pulmonary arterial smooth muscle cells (PASMC) proliferation and to determine the effect of AMPK activation on PDGF-induced PASMC proliferation and its underlying mechanisms. PDGF activated PI3K/Akt/mTOR signaling pathway, and this in turn up-regulated Skp2 and consequently reduced p27 leading to PASMC proliferation. Prior incubation of PASMC with metformin induced a dramatic AMPK activation and significantly blocked PDGF-induced cell proliferation. PASMC lacking AMPKα2 were resistant to the inhibitory effect of metformin on PDGF-induced cell proliferation. Metformin did not affect Akt activation but blocked mTOR phosphorylation in response to PDGF; these were accompanied by the reversion of Skp2 up-regulation and p27 reduction. Our study suggests that the activation of AMPK negatively regulates mTOR activity to suppress PASMC proliferation and therefore has a potential value in the prevention and treatment of pulmonary hypertension by negatively modulating pulmonary vascular remodeling.
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Medical College, Xi⿿an Jiaotong University, Xi⿿an, Shaanxi 710061, PR China. Electronic address: manxiangli@hotmail.com.
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D044786:S-Phase Kinase-Associated Proteins; D058570:TOR Serine-Threonine Kinases
keywords: AMPK; Pulmonary arterial smooth muscle cells; Skp2; mTOR; p27