title: Simvastatin inhibits sphingosylphosphorylcholine-induced differentiation of human mesenchymal stem cells into smooth muscle cells.
abstract: Sphingosylphosphorylcholine (SPC) induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) into smooth muscle-like cells expressing α-smooth muscle actin (α-SMA) via transforming growth factor-β1/Smad2- and RhoA/Rho kinase-dependent mechanisms. 3-Hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors (statins) have been known to have beneficial effects in the treatment of cardiovascular diseases. In the present study, we examined the effects of simvastatin on the SPC-induced α-SMA expression and Smad2 phosphorylation in hASCs. Simvastatin inhibited the SPC-induced α-SMA expression and sustained phosphorylation of Smad2 in hASCs. SPC treatment caused RhoA activation via a simvastatin-sensitive mechanism. The SPC-induced α-SMA expression and Smad2 phosphorylation were abrogated by pretreatment of the cells with the Rho kinase inhibitor Y27632 or overexpression of a dominant negative RhoA mutant. Furthermore, SPC induced secretion of TGF-β1 and pretreatment with either Y27632 or simvastatin inhibited the SPC-induced TGF-β1 secretion. These results suggest that simvastatin inhibits SPC-induced differentiation of hASCs into smooth muscle cells by attenuating the RhoA/Rho kinase-dependent activation of autocrine TGF-β1/Smad2 signaling pathway.
authors: Medical Research Center for Ischemic Tissue Regeneration, Pusan National University, Yangsan 626-770, Korea.
authors: Kyung Hye
authors: KH
authors: Kim
authors: Young Mi
authors: YM
authors: Kim
authors: Mi Jeong
authors: MJ
authors: Lee
authors: Hyun-Chang
authors: HC
authors: Ko
authors: Moon-Bum
authors: MB
authors: Kim
authors: Jae Ho
authors: JH
authors: Kim
mesh_terms: D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D011725:Pyridines; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C108830:Y 27632; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine