DOI: 10.5176/978-981-08-8669-1_SCR2011_15

Authors: Rouel S. Roque

Retinoic acid (RA), the biologically active form of vitamin A and potent inducer of tissue differentiation, regulates cardiogenesis, however, the mechanisms remain unclear. In this study, we dissected the molecular pathways surrounding RAinduced differentiation in cultured h9c2 cells, a cardioblast cell line derived from the embryonic rat heart. Incubation with RA enhanced the transcriptional activity of the muscle-restricted gene regulatory protein myocyte enhancer factor 2 (MEF2), and induced a time/concentration-dependent increase in expression of cardiomyocyte biomarkers including cardiac myosin heavy chain (cMHC) and ventricular myosin light chain-2 (vMLC2). Forced expression of dominant negative MEF2C or buffering Ca2+ with EGTA (extracellular) and Bapta-AM (intracellular) abrogated the described response. Interestingly, RA treatment augmented intracellular calcium levels, a rise eradicated through pharmacological inhibition of L-type calcium channels (LTCC) with nifedipine or verapamil. Furthermore, LTCC inhibition diminished MEF2 transcriptional events and appearance of cMHC and vMLC2 proteins in response to RA. Among the signaling molecules responsive to alterations in Ca2+ homeostasis, calcineurin appeared to play a major role. Inhibition of calcineurin FK506, cyclosporine A, or CAIN, but not of PKC or CaM kinase, suppressed RA-induced differentiation and MEF2 activity. In conclusion, our findings demonstrate that RA promotes development of aventricular myocyte phenotype in cardiac myoblasts via MEF2C utilizing a Ca2+/calcineurin-mediated RA receptor independent signaling cascade triggered in part by LTCC. These results provide new evidence to the nature of retinoid signaling and identify LTCC as a potential target for pharmacological intervention in regenerative medicine.

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