Activation of FGF1B Promoter and FGF1 Are Involved in Cardiogenesis Through the Signaling of PKC, but Not MAPK.

Heart disease is the leading cause of human death in the 21st century. Heart transplantation is a promising way to treat this. Because donor resources are limited, cell-based therapy has been developed as an alternative. Therefore, genes that trigger cardiogenesis could have potential in the treatment of heart disease. Fibroblast growth factor 1 (FGF1) is reported to stimulate cardiomyocyte proliferation under conditions of myocardial infarction, but little is known about its function during cardiac differentiation. In this study, we established an in vitro cardiogenesis model through a reliable chemical induction protocol to determine whether FGF1 and its gene expression are involved in cardiogenesis. Oxytocin, not only a well-known hormone but also a cardiac differentiation inducer, was used in a mouse embryonic stem cell line, E14Tg2a, to achieve cardiac differentiation. After differentiation, beating cell clusters appeared and the expression of FGF1B mRNA was upregulated in the late differentiation stage (differentiation days 8-14). Interestingly, FGF1B expression patterns during cardiac differentiation were similar to those of a mature cardiomyocyte marker, troponin T2, cardiac. The blockage of FGF1-FGF receptor (FGFR) signaling reduced not only the appearance of beating cluster formation but also the expression levels of cardiomyocyte-associated genes. Moreover, by investigating FGF1 downstream signaling cascades, we observed that the efficiency of beating cluster formation was mainly regulated through the FGF1-FGFR-PKC signaling axis. Taken together, we provide evidence to support that FGF1 could regulate cardiogenesis primarily through the protein kinase C signaling, but not through the mitogen-activated protein kinase signaling, pathway.