title: Mibefradil suppresses the proliferation of pulmonary artery smooth muscle cells.
abstract: Intracellular Ca(2+) levels play a critical role in the regulation of vasodilation and vasoconstriction by stimulating pulmonary artery smooth muscle cell (PASMC) proliferation, which is important in the pathogenesis of pulmonary arterial hypertension (PAH); however, L-type Ca(2+) channel antagonists are useful in only few patients with PAH. The present study sought to assess the effect of mibefradil, which blocks T-type Ca(2+) channels, on PASMC proliferation and Ca(2+) channel profile. Human PASMCs were stimulated with 25 ng/mL platelet-derived growth factor-BB (PDGF-BB) with and without 10 µM mibefradil or 100 nM sildenafil. After 48 or 72 h, PASMC proliferation and Ca(2+) channel expression were assessed by MTT assays and western blot analysis, respectively. PDGF-BB-induced PASMC proliferation at 72 h (p<0.01), which was inhibited by both sildenafil and mibefradil (p<0.01). Transient receptor potential Ca(2+) channel 6 (TRPC6) expression was significantly increased with PDGF-BB stimulation (p=0.009); however, no changes in TRPC1, TRPC3, CAV1.2, and CAV3.2 levels were observed. Although both TRPC1 and CAV1.2 expression levels were increased in PDGF-stimulated PASMCs on mibefradil and sildenafil treatment, it was not statistically significant (p=0.086 and 1.000, respectively). Mibefradil inhibits PDGF-BB-stimulated PASMC proliferation; however, the mechanism through which it functions remains to be determined. Further studies are required to elucidate the full therapeutic value of mibefradil for PAH.
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Hong-Hong
authors.initials: HH
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Li-Jian
authors.initials: LJ
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020748:Mibefradil / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology*; D050052:TRPC Cation Channels / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D000077214:Becaplermin; D020748:Mibefradil; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium