title: Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells.
abstract: Inhibition of proteasome function has been shown to suppress several types of cells proliferation; this study investigates whether this also occurs in pulmonary artery smooth muscle cells (PASMCs) and its potential mechanisms. Serotonin induced 4.27-fold increase in DNA synthesis in PASMCs, and this effect was dose-dependently blocked by prior incubation of cells with MG132, a specific proteasome inhibitor. Inhibition of proteasome function did not modulate serotonin-triggered pro-proliferation signaling pathways, such as extracellular signal-regulated mitogen-activated protein kinase (ERK1/2 MAPK) and Ras homolog gene family member A (RhoA). Further study indicated that treatment of PASMCs with serotonin reduced p21(WAF1) protein level but not its transcription; this was reversed by inhibiting ERK1/2 MAPK or RhoA cascade equally. In addition, MG132 increased the protein level of p21(WAF1) in a dose-dependent manner in the presence of serotonin, 10 μM MG132 led to a 4.2-fold increase in p21(WAF1) protein level, and this effect was not mediated by increasing p21(WAF1) mRNA level. More importantly, cell lacking p21(WAF1) by siRNA transfection abolished the inhibitive effect of MG132 on cells proliferation. Our study suggests that accumulation of p21(WAF1) protein level caused by proteasome inhibition particularly mediated its inhibitive effect on PASMCs proliferation, and inhibition of proteasome function might have potential value in the treatment of pulmonary hypertension.
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, No.157, West 5th Road, Xi'an, Shaanxi, 710004, People's Republic of China. manxiangli@hotmail.com
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.forename: Xilin
authors.initials: X
authors.lastname: Dong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Sun
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Li
authors.forename: Jiyin
authors.initials: J
authors.lastname: He
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D007976:Leupeptins / Q000008:administration & dosage / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D025801:Ubiquitin; D012701:Serotonin; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde