Abstract 1373: Postnatal Ectopic Overexpression of Bmp10 in Ventricular Myocardium Disrupts Cardiac Developmental Hypertrophic Growth
Cardiac hypertrophies have traditionally been classified into physiological and pathological hypertrophy and regarded as adaptive responses to hemodynamic load in postnatal heart when cardiomyocytes irreversibly withdraw from cell cycle activity. In contrast, cardiac developmental hypertrophic growth is recognized as a part of cardiac morphogenetic process that is irrelevant to cardiac working load. However, this biological event is often difficult to separate from physiological cardiac hypertrophy. Its biological significance has not been well addressed mainly due to the difficulty to create an experimental condition for testing the growth potential of a functioning heart in the absence of hemodynamic load. Recently, we have generated a novel transgenic mouse model (αMHC-Bmp10) in which cardiac specific growth factor bone morphogenetic protein 10 (Bmp10) was re-activated in early postnatal myocardium. αMHC-Bmp10 mice have normal cardiac development during embryogenesis, but give rise to smaller hearts (less than half of the normal size) with 100% penetrance. Morphometric and cell cycle analysis of cardiomyocytes demonstrated that the severely compromised cardiac growth in αMHC-Bmp10 mice was solely due to defect in cellular hypertrophic growth. Physiological analysis further indicated that their response to both the physiological (chronic swimming training) and pathological hypertrophic stimuli remained normal. Our findings suggest that Bmp10 over-expression blocks cardiac developmental hypertrophic growth in early postnatal life. The compromised developmental hypertrophy also had a profound effect on cardiac function. Both the ejection fraction and fraction shortening were significantly increased in αMHC-Bmp10 mice. This is the first demonstration that cardiac developmental hypertrophic growth can be specifically modified genetically and separated from physiological and pathological hypertrophy. Systematic analyses of BMP-mediated signaling pathways further suggested a novel genetic pathway in regulating cardiac developmental hypertrophy.