Identifying the key factor mediating pathological
cardiac hypertrophy is critically important for developing the strategy to protect against
heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in
cardiac hypertrophy, apoptosis, and
fibrosis in experimentally pathological
cardiac hypertrophy. The in vivo pathological
cardiac hypertrophy models were induced by pressure-overload and
angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological
cardiac hypertrophy, but not in swimming exercise-induced physiological
cardiac hypertrophy in mice. BMP4 expression also increased in Ang II-induced cardiomyocyte
hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte
hypertrophy, apoptosis, and cardiac
fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II-induced cardiomyocyte
hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte
hypertrophy and apoptosis was through increasing
NADPH oxidase 4 expression and
reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated
hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload-induced
cardiac hypertrophy in mice in vivo. The plasma BMP4 level of
heart failure patients was increased compared with that of subjects without
heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological
cardiac hypertrophy.