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L‐type calcium channels modulate retinoic acid‐induced MEF2 activity and expression of cardiac specific genes
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.588.3
Subject(s) - mef2 , calcineurin , mef2c , microbiology and biotechnology , l type calcium channel , retinoic acid , myocyte , orai1 , chemistry , myogenesis , calcium channel , biology , gene expression , calcium , enhancer , transplantation , biochemistry , medicine , gene , endoplasmic reticulum , stim1 , organic chemistry
Purpose: Cardiomyocyte differentiation is an intricate process indispensable for cardiogenesis and myocardial regeneration. In this study, we examined the signaling components necessary for retinoic acid (RA), a potent regulator of cardiac growth, to generate a myocyte phenotype in h9c2 cardioblasts. Methods: H9c2 cells exposed to RA were characterized for expression of cardiac‐specific proteins myosin heavy chain (cMHC) and ventricular myosin light chain‐2 (vMLC2). L‐type Ca 2+ channel (LTCC), calcineurin, and MEF2 activity was documented with luciferase‐reporters, pharmacological inhibitors, and/or dominant negative (dn) plasmids. Results: RA treatment augmented intracellular calcium levels, enhanced transcriptional activity of MEF2, and increased expression of cMHC and vMLC2. The effects of RA were attenuated by buffering Ca 2+ with EGTA or Bapta‐AM, blockade of LTCC with nifedipine, and inhibition of calcineurin with FK506. Forced overexpression of dn‐MEF2C or CAIN, an endogenous inhibitor of calcineurin, abrogated RA‐induced differentiation and MEF2 activity. Conclusions: RA promotes development of a cardiomyocyte phenotype through a Ca 2+ ‐dependent pathway involving LTCC‐calcineurin‐MEF2C. These results provide novel targets of retinoid signaling that could prove useful for programming stem cell differentiation in the treatment of heart disease.