Bone morphogenetic protein-4 contributes to the down-regulation of Kv4.3 K+ channels in pathological cardiac hypertrophy

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.