title: Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy.
abstract: 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.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Baojian Rd 157, Harbin 150086, Heilongjiang Province, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Rong
authors.initials: R
authors.lastname: Huo
authors.forename: Yue
authors.initials: Y
authors.lastname: Sheng
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
authors.forename: Hui-Bin
authors.initials: HB
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Cheng-Bo
authors.initials: CB
authors.lastname: Li
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Guo
authors.forename: Jiu-Xin
authors.initials: JX
authors.lastname: Zhu
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000097:blood / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000097:blood; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010805:Physical Conditioning, Animal / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D017382:Reactive Oxygen Species; D000804:Angiotensin II