Kv4.3 expression abrogates and reverses norepinephrine-induced myocyte hypertrophy by CaMKII inhibition

Background: Down-regulation of Kv4.3 protein is a general feature of cardiac hypertrophy. Based on our recent studies, we propose that Kv4.3 reduction may be a hypertrophic stimulator. Objective: We tested whether Kv4.3 expression can prevent or reverse cardiac hypertrophy induced by nor epinephrine (NE). Methods and results: Incubation of 20 mu M NE in cultured neonatal rat ventricular myocytes (NRVMs) for 48 h and 96 h induced myocyte hypertrophy in a time-dependent manner, characterized by progressive increase in cell size, protein/DNA ratio, ANP and BNP, along with an progressive increase in the activity of CaMKII and calcineurin and reduction of Kv4.3 mRNA and proteins. Interestingly, PICA-dependent phosphorylation of phospholamban (PLB) at Ser16 was increased at 48 h but reduced to the basal level at 96 h NE incubation. CaMKII inhibitors KN93 and AIP blunted NE-induced hypertrophic response and caused regression of hypertrophy, which is associated with a reduction of CaMKII activity and calcineurin expression. Kv4.3 expression completely suppressed the development of NE-induced hypertrophy and led to a regression in the hypertrophic myocytes. These effects were accompanied by a reduction in CaMKII autophosphorylation, PLB phosphorylation at Thr-17 without changing PLB phosphorylation at Ser-16. NFATc3 was also reduced by Kv4.3 expression. Conclusions: Our results demonstrated that Kv4.3 reduction is an important mediator in cardiac hypertrophy development via excessive CaMKII activation and that Kv4.3 expression is likely a potential therapeutic strategy for prevention and reversion of adrenergic stress-induced cardiac hypertrophy.