期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 126, 期 -, 页码 77-85出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2018.11.011
关键词
I-to channel; Kv4.3; Hypertrophy; Calcineurin; CaMKII; And myocytes
资金
- National Natural Science Foundation of China (NSFC, China) [81270304, 81873507, 81420108004]
- National Institutes of Health (USA) [R01HL-083271]
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.
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