title: Bone morphogenetic protein-4 contributes to the down-regulation of Kv4.3 K+ channels in pathological cardiac hypertrophy.
abstract: Kv4.3 K(+) channels contributing to Ito are involved in the repolarization of cardiac action potential. Kv4.3 K(+) channels decrease in pathological cardiac hypertrophy, but the mechanism remains unclear. Our previous study found that the expression of bone morphogenetic protein 4 (BMP4) increased in pressure-overload and Ang II constant infusion induced cardiac hypertrophy. Since the downregulation of Kv4.3 K(+) channels and the upregulation of BMP4 simultaneously occur in pathological cardiac hypertrophy, we hypothesize that the up-regulated BMP4 would contribute to the downregulation of Kv4.3 K(+) channels in cardiac hypertrophy. We found that BMP4 treatment reduced Kv4.3 but not Kv4.2 and Kv1.4 K(+) channel protein expression, and BMP4-induced decrease of Kv4.3 K(+) channel protein expression was reversed by BMP4 inhibitor noggin and DMH1 in cultured cardiomyocytes in vitro. BMP4-induced decrease of Kv4.3 K(+) channel protein expression was also reversed by the NADPH oxidase inhibitor apocynin and the radical scavenger tempol. In in vivo transverse aortic constriction (TAC)-induced cardiac hypertrophy, constant infusion of DMH1 completely rescued TAC-induced down-regulation of Kv4.3 K(+) channel protein expression. We conclude that BMP4 contributes to the downregulation of Kv4.3 K(+) channels in pathological cardiac hypertrophy and the underlying mechanism might be through increasing ROS production.
authors.affiliation: Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin 150086, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Yue
authors.initials: Y
authors.lastname: Sheng
authors.forename: Rong
authors.initials: R
authors.lastname: Huo
authors.forename: Chao-Wei
authors.initials: CW
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Shan-Liang
authors.initials: SL
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
mesh_terms: D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D006332:Cardiomegaly / Q000503:physiopathology*; D017931:DNA Primers; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000502:physiology*
chemical_list: C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D017931:DNA Primers; D051672:Shal Potassium Channels
keywords: Bone morphogenetic protein-4; Hypertrophy; Kv4.3 K(+) channel