title: Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1.
abstract: Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which has been shown to ameliorate the development of pulmonary hypertension in animal model by suppression of pulmonary artery smooth muscle cells (PASMCs) proliferation, yet its underlying molecular mechanisms are not completely understood. In this study, we show that simvastatin dose-dependently inhibited serotonin-stimulated PASMCs proliferation. This was accompanied with the parallel induction of heme oxyganase-1 (HO-1) and upregulation of p21(WAF1). More importantly, we found that Tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, could block the effect of simvastatin on inhibition of cell proliferation in response to serotonin and abolish simvastatin-induced p21(WAF1) expression. The inhibitive effect of simvastatin on cell proliferation was also significantly suppressed by silencing p21(WAF1) with siRNA transfection. The extent of effect of SnPP on inhibition of cell proliferation was similar to that of lack of p21(WAF1) by siRNA transfection. Taken together, our study suggests that simvastatin inhibits PASMCs proliferation by sequential upregulation of HO-1 and p21(WAF1) to benefit pulmonary hypertension.
authors: Respiratory Diseases Research Center, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China. manxiangli@hotmail.com
authors: Manxiang
authors: M
authors: Li
authors: Yuan
authors: Y
authors: Liu
authors: Hongyang
authors: H
authors: Shi
authors: Yonghong
authors: Y
authors: Zhang
authors: Guizuo
authors: G
authors: Wang
authors: Jing
authors: J
authors: Xu
authors: Jiamei
authors: J
authors: Lu
authors: Dexin
authors: D
authors: Zhang
authors: Xinming
authors: X
authors: Xie
authors: Dong
authors: D
authors: Han
authors: Yuanyuan
authors: Y
authors: Wu
authors: Shaojun
authors: S
authors: Li
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D015854:Up-Regulation
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034741:RNA, Small Interfering; D012701:Serotonin; D019821:Simvastatin; D051547:Heme Oxygenase-1