Activation of AMPK α2 inhibits airway smooth muscle cells proliferation.
The aims of the present study were to examine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on airway smooth muscle cells (ASMCs) proliferation and to address its potential mechanisms. Platelet derived growth factor (PDGF) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, and this in turn up-regulated S-phase kinase-associated protein 2 (Skp2) and consequently reduced cyclin dependent kinase inhibitor 1B (p27) leading to ASMCs proliferation. Pre-incubation of cells with metformin, an AMPK activator, blocked PDGF-induced activation of mTOR and its downstream targets changes of Skp2 and p27 without changing Akt phosphorylation and inhibited ASMCs proliferation. Transfection of ASMCs with AMPK α2-specific small interfering RNA (siRNA) reversed the effect of metformin on mTOR phosphorylation, Skp2 and p27 protein expression and cell proliferation. Our study suggests that activation of AMPK, particularly AMPK α2, negatively regulates mTOR activity to suppress ASMCs proliferation and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: 443606290@qq.com.
Lu
L
Liu
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: 287842481@qq.com.
Yilin
Y
Pan
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: wyshzl@163.com.
Yang
Y
Song
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: 376687378@qq.com.
Xiaofan
X
Su
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: 494228013@qq.com.
Rui
R
Ke
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: beautiful012@163.com.
Lan
L
Yang
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. Electronic address: lgao2@jhmi.edu.
Li
L
Gao
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: manxiangli@hotmail.com.
Manxiang
M
Li
D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001980:Bronchi / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008687:Metformin / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014132:Trachea / Q000166:cytology*
D055372:AMP-Activated Protein Kinases; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D058570:TOR Serine-Threonine Kinases; C413374:p27 antigen; C543928:Prkaa2 protein, rat
AMPK; Airway smooth muscle cells; LY294002 (PubChem CID: 11957589); MTOR; P27; Rapamycin (PubChem CID: 5284616); Skp2