Copyright © 2007, European Society of Cardiology
Bone morphogenetic protein-2 acts upstream of myocyte-specific enhancer factor 2a to control embryonic cardiac contractility
aDepartment of Molecular Genetics, Shanghai Medical School and Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, 138 Yi Xueyuan Road, Shanghai, 200032, P.R. China
bDepartment of Medicine, Pharmacology and Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
cDepartment of Physiology and Pathophysiology, Shanghai Medical School, Fudan University, Shanghai, 200032, P.R. China
dElectron Microscope Laboratory, Shanghai Medical School, Fudan University, Shanghai, 200032, P.R. China
eChildren's Hospital, Fudan University, Shanghai, 200032, P.R. China
* Corresponding author. Tel.: +86 21 5423 7739; fax: +86 21 6403 3738. Email address: hysong{at}shmu.edu.cn
Objective: 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).
Methods: 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.
Results: 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.
Conclusions: 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.
KEYWORDS Developmental biology; Contractile function; Heart failure; Cardiomyopathy
Abbreviations: MEF2A, myocyte-specific enhancer factor 2A • hpf, hours post fertilization • GFP, green fluorescent protein • MO, morpholino • V, ventricle • A, atrium • BMP, bone morphogenetic protein • NRVC, neonatal rat ventricular cardiomyocytes • VSF, ventricular shortening fraction • PLC
1, phospholipase C 1 • VEGF, vascular endothelial growth factor • vmhc, ventricular myosin heavy chain • amhc, atrial myosin heavy chain • cmlc2, cardiac myosin light chain 2 • ANF, atrial natriuretic factor • FGF-8, fibroblast growth factor-8.
The GenBank accession numbers for rat MEF2A and zebrafish MEF2A are DQ 323505 and DQ 323506, respectively.
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