Abstract 19016: ALK2 and ALK3 BMP Type I Receptors Are Required for the Development of Cardiac Hypertrophy

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Bone Morphogenetic Proteins (BMP) signaling is required for the development of cardiac hypertrophy. BMP signaling mediates its action via BMP type I and type II receptors. We sought to determine which type I receptors are required for cardiac hypertrophy. We studied BMP signaling in neonatal rat cardiomyocytes (NRCs) stimulated with phenylephrine (PE) or isoproterenol (ISO). In comparison with untreated NRCs, PE (10 μM) and ISO (10 μM) induced hypertrophy, as reflected by increases in cell size (457±50 and 401±35 vs 254±23 μm2, p<0.01) and expression of the gene encoding B-type natriuretic peptide (NPPB; 4.0±1.0 and 3.2±0.8-fold, p<0.01). PE and ISO induced expression of genes specifying BMP2 (6.7±0.5 and 5.6±0.6-fold), BMP7 (4.1±0.4 and 3.6±0.9-fold), and the BMP target gene, Id-1, (3.7±0.1 and 4.2±1.0-fold, p<0.001). PE and ISO also induced phosphorylation of BMP-responsive Smads 1 and 5 and increased activity of a BMP response element-luciferase reporter (14.5±0.8 and 11.9±1.1 vs 5.4±0.4, p<0.01). Incubation of NRCs with the BMP inhibitors, LDN193189 (100 nM) or noggin (100 ng/ml), markedly suppressed the ability of PE and ISO to increase cell size, NPPB gene expression, and Smad1/5 phosphorylation. qRT-PCR analysis revealed that ALK2 and ALK3 were highly expressed in NRC, whereas ALK1 and ALK6 were expressed at very low levels. siRNA-mediated silencing of ALK2 or ALK3, but not ALK1 or ALK6, blocked PE-induced hypertrophy in NRCs. Using cardiomyocytes from ALK1flox/flox and ALK2flox/flox neonatal mice infected with Ad-Cre (to delete the floxed allele) or Ad-RFP (as a control) revealed that PE-induced hypertrophy requires Alk2 but not Alk1. Based on these observations, we conclude that BMP signaling is upregulated in NRCs in response to hypertrophic stimuli. ALK2 and ALK3 appear to be the BMP type I receptors which are required for the development of hypertrophy in neonatal cardiac myocytes.