Overexpression of Bone Morphogenetic Protein 10 in Myocardium Disrupts Cardiac Postnatal Hypertrophic Growth

Abstract

Postnatal cardiac hypertrophies have traditionally been classified into physiological or pathological hypertrophies. Both of them are induced by hemodynamic load. Cardiac postnatal hypertrophic growth is regarded as a part of the cardiac maturation process that is independent of the cardiac working load. However, the functional significance of this biological event has not been determined, mainly because of the difficulty in creating an experimental condition for testing the growth potential of functioning heart in the absence of hemodynamic load. Recently, we generated a novel transgenic mouse model (␣MHC-BMP10) in which the cardiacspecific growth factor bone morphogenetic protein 10 (BMP10) is overexpressed in postnatal myocardium. These ␣MHC-BMP10 mice appear to have normal cardiogenesis throughout embryogenesis, but develop to smaller hearts within 6 weeks after birth. ␣MHC-BMP10 hearts are about half the normal size with 100% penetrance. Detailed morphometric analysis of cardiomyocytes clearly indicated that the compromised cardiac growth in ␣MHC-BMP10 mice was solely because of defect in cardiomyocyte postnatal hypertrophic growth. Physiological analysis further demonstrated that the responses of these hearts to both physiological (e.g. exercise-induced hypertrophy) and pathological hypertrophic stimuli remain normal. In addition, the ␣MHC-BMP10 mice develop subaortic narrowing and concentric myocardial thickening without obstruction by four weeks of age. Systematic analysis of potential intracellular pathways further suggested a novel genetic pathway regulating this previously undefined cardiac postnatal hypertrophic growth event. This is the first demonstration that cardiac postnatal hypertrophic growth can be specifically modified genetically and dissected out from physiological and pathological hypertrophies.Hypertrophic growth of cardiomyocytes plays an important role in determining the size of the heart (1, 2). Cardiomyocyte hypertrophy has usually been regarded as an adaptive response to hemodynamic load in postnatal hearts when cardiomyocytes irreversibly withdraw from cell cycle activity (3, 4). As a part of the normal developmental process, the cell cycle activity of cardiomyocyte declines rapidly upon terminal differentiation and maturation. At birth, the majority of cardiomyocytes (97%) stops proliferation and remains in G 0 /G 1 phase (5, 6). This cardiomyocyte cell cycle withdraw is considered a key phenomenon in the heart switching from hyperplastic growth to hypertrophic growth (3).Cardiac hypertrophy has traditionally been classified as pathological or physiological (7). For example, persistent pressure or volume overload caused by disease conditions, such as hypertension, stenotic cardiac valve disorders, and genetic defects in contractile proteins, can induce cardiac pathological hypertrophy, which can be associated with diminished heart function and eventual heart failure (8, 9). In contrast, physiological cardiac hypertrophy is a normal beneficial adaptive response of the heart to phys...

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