title: Simvastatin-enhanced expression of promyogenic nuclear factors and cardiomyogenesis of murine embryonic stem cells.
abstract: A combination of statin and stem cell therapies has been shown to benefit in experimental models of myocardial infarction. This study tests whether treatment with simvastatin has a direct impact on the cardiomyogenic development of murine embryonic stem cells (ESCs) in embryoid bodies. In a concentration-dependent manner, simvastatin treatment enhanced expression of several promyogenic nuclear transcription factors, including GATA4, Nkx2.5, DTEF-1 and myocardin A. The statin-treated cells also displayed higher levels of cardiac proteins, including myosin, α-actinin, Ryanodine receptor-2, and atrial natriuretic peptide, and they developed synchronized contraction. The statin's promyogenic effect was partially diminished by the addition of the two isoprenoids FPP and GGPP, which are intermediates of cholesterol synthesis. Thus, simvastatin treatment enhances ESC myogenesis during early development perhaps via a mechanism inhibiting the mevalonate-FPP/GGPP pathway.
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Medical School at Houston, Houston, TX USA; The Department of Obstetrics and Gynecology, Ruijin Hospital, Jiao-Tong University Medical School, Shanghai, China; Texas Heart Institute, Houston, TX, USA.
authors.forename: ChenMin
authors.initials: C
authors.lastname: Yang
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Medical School at Houston, Houston, TX USA; Texas Heart Institute, Houston, TX, USA.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Madonna
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Medical School at Houston, Houston, TX USA; Texas Heart Institute, Houston, TX, USA.
authors.forename: Yangxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Department of Cardiovascular Medicine, Ruijin Hospital, Jiao-Tong University Medical School, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Department of Cardiovascular Medicine, Ruijin Hospital, Jiao-Tong University Medical School, Shanghai, China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Shen
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Medical School at Houston, Houston, TX USA; Texas Heart Institute, Houston, TX, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: McNamara
authors.affiliation: FuWai Cardiovascular Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Medical School at Houston, Houston, TX USA; Texas Heart Institute, Houston, TX, USA. Electronic address: yong-jian.geng@uth.tmc.edu.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D050991:GATA4 Transcription Factor / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D024510:Muscle Development / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C484469:Nkx2-5 protein, mouse; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D000091262:TEA Domain Transcription Factors; C432156:Tead3 protein, mouse; D014157:Transcription Factors; C004808:farnesyl pyrophosphate; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate
keywords: ANP; Cholesterol synthesis; EBs; ESCs; FPP; GGPP; MHC; MLC; Myogenesis; Statin; Stem cells; Transcription; atrium natriuretic peptide; embryoid bodies; embryonic stem cells; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; myosin heavy chain; myosin light chain