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.