title: Adenosine monophosphate-activated protein kinase is required for pulmonary artery smooth muscle cell survival and the development of hypoxic pulmonary hypertension.
abstract: Human pulmonary artery smooth muscle cells (HPASMCs) express both adenosine monophosphate-activated protein kinase (AMPK) α1 and α2. We investigated the distinct roles of AMPK α1 and α2 in the survival of HPASMCs during hypoxia and hypoxia-induced pulmonary hypertension (PH). The exposure of HPASMCs to hypoxia (3% O2) increased AMPK activation and phosphorylation, and the inhibition of AMPK with Compound C during hypoxia decreased their viability and increased lactate dehydrogenase activity and apoptosis. Although the suppression of either AMPK α1 or α2 expression led to increased cell death, the suppression of AMPK α2 alone increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. It also resulted in the decreased expression of myeloid cell leukemia sequence 1 (MCL-1). The knockdown of MCL-1 or MCL-1 inhibitors increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. On the other hand, the suppression of AMPK α1 expression alone prevented hypoxia-mediated autophagy. The inhibition of autophagy induced cell death in HPASMCs. Our results suggest that AMPK α1 and AMPK α2 play differential roles in the survival of HPASMCs during hypoxia. The activation of AMPK α2 maintains the expression of MCL-1 and prevents apoptosis, whereas the activation of AMPK α1 stimulates autophagy, promoting HPASMC survival. Moreover, treatment with Compound C, which inhibits both isoforms of AMPK, prevented and partly reversed hypoxia-induced PH in mice. Taking these results together, our study suggests that AMPK plays a key role in the pathogenesis of pulmonary arterial hypertension, and AMPK may represent a novel therapeutic target for the treatment of pulmonary arterial hypertension.
authors.affiliation: 1 Department of Pediatrics.
authors.forename: Joyce Christina F
authors.initials: JC
authors.lastname: Ibe
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Tianji
authors.initials: T
authors.lastname: Chen
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.forename: Guofei
authors.initials: G
authors.lastname: Zhou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D000249:Adenosine Monophosphate; D055372:AMP-Activated Protein Kinases