Bone morphogenetic protein-2 acts upstream of myocyte-specific enhancer factor 2a to control embryonic cardiac contractility

• Published in: Cardiovascular research 2007-05, Vol.74 (2), p.290-303
• Main Authors: WANG, Yue-Xiang, QIAN, Lin-Xi, DONG LIU, YAO, Ling-Ling, QIU JIANG, ZHANG YU, GUI, Yong-Hao, ZHONG, Tao P, SONG, Hou-Yan
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Base Sequence; Biological and medical sciences; Blotting, Western; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - analysis; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - metabolism; Cardiology. Vascular system; Carrier Proteins - pharmacology; Cells, Cultured; Gene Expression Regulation - drug effects; Genetic Engineering; Heart; Heart - embryology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; MADS Domain Proteins - analysis; MADS Domain Proteins - genetics; MADS Domain Proteins - metabolism; Medical sciences; MEF2 Transcription Factors; Molecular Sequence Data; Myocardial Contraction - physiology; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - physiology; Myogenic Regulatory Factors - analysis; Myogenic Regulatory Factors - genetics; Myogenic Regulatory Factors - metabolism; Organisms, Genetically Modified; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering - administration & dosage; Signal Transduction - physiology; Transforming Growth Factor beta - analysis; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Zebrafish - embryology; Zebrafish - metabolism; Zebrafish Proteins - genetics
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2007.02.007

Cardiac contractility is regulated tightly as an extrinsic and intrinsic homeostatic mechanism to the heart. The molecular basis of the intrinsic system is largely unknown. Here, we test the hypothesis that bone morphogenetic protein-2 (BMP-2) mediates embryonic cardiac contractility upstream of myocyte-specific enhancer factor 2A (MEF2A). The BMP-2 and MEF2A expression pattern was analyzed by RT-PCR, Western blotting, whole-mount in situ hybridization, and an in vivo transgenic approach. The cardiac phenotype of BMP-2 and MEF2A knock-down zebrafish embryos was analysed. Cardiac contractions were recorded with a video camera. Myofibrillar organization was observed with transmission electron microscopy. Gene expression profiles were performed by quantitative real-time PCR analysis. We demonstrate that BMP-2 and MEF2A are co-expressed in embryonic and neonatal cardiac myocytes. Furthermore, we provide evidence that BMP-2 is required for cardiac contractility in vitro and in vivo and that MEF2A expression can be activated by BMP-2 signaling in neonatal cardiomyocytes. BMP-2 is involved in the assembly of the cardiac contractile apparatus. Finally, we find that exogenous MEF2A is sufficient to rescue ventricular contractility defects in the absence of BMP-2 function. In all, these observations indicate that BMP-2 and MEF2A are key components of a pathway that controls the cardiac ventricular contractility and suggest that the BMP2-MEF2A pathway can offer new opportunities for the treatment of heart failure.