title: Endothelin-1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells.
abstract: Endothelin-1 (ET-1) dose-dependently increased HIF1α expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET-1-induced HIF1α expression. The maximum effect of ET-1 was similar to that caused by proteasome inhibitor MG132. Further study indicates that ET-1 also dose-dependently stimulated calcineurin activation, specific calcineurin inhibitor cyclosporine A (CsA), abolished ET-1-induced HIF1α elevation, and reversed ET-1-induced RACK1 (receptor of activated protein kinase C 1) de-phosphorylation. Endothelin receptor A was found to specifically mediate the effects of ET-1. To examine whether RACK1 is particularly involved in proteasome-dependent HIF1α degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1α protein level. Taken together, our study suggests that ET-1 suppressed proteasome-dependent HIF1α degradation by calcineurin-dependent RACK1 de-phosphorylation.
authors.affiliation: Respiratory Diseases Research Center, Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China. manxiangli@hotmail.com
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Faguang
authors.initials: F
authors.lastname: Jin
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Sun
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.forename: Hongyang
authors.initials: H
authors.lastname: Shi
authors.forename: Xingtang
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D019332:Endothelin-1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007976:Leupeptins; D011480:Protease Inhibitors; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D017466:Receptors, Endothelin; D016572:Cyclosporine; D019703:Calcineurin; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde