Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, China; Medical Research Institute, Wuhan University, China; Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
J Mol Cell Cardiol. 2019 Jan;126:77-85. doi: 10.1016/j.yjmcc.2018.11.011. Epub 2018 Nov 18.
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.
We tested whether Kv4.3 expression can prevent or reverse cardiac hypertrophy induced by norepinephrine (NE).
Incubation of 20 μM 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, PKA-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.
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.
Kv4.3 蛋白的下调是心脏肥大的普遍特征。基于我们最近的研究，我们提出 Kv4.3 的减少可能是一种肥大刺激物。
我们测试了 Kv4.3 的表达是否可以预防或逆转去甲肾上腺素（NE）诱导的心肌肥厚。
在培养的新生大鼠心室肌细胞（NRVM）中孵育 20 μM NE 48 h 和 96 h 以时间依赖性方式诱导心肌肥厚，特征为细胞大小、蛋白/DNA 比、ANP 和 BNP 逐渐增加，同时 CaMKII 和钙调神经磷酸酶的活性逐渐增加，Kv4.3 mRNA 和蛋白减少。有趣的是，PKA 依赖性 PLB 丝氨酸 16 磷酸化在 48 h 时增加，但在 96 h NE 孵育时降低至基础水平。CaMKII 抑制剂 KN93 和 AIP 减弱了 NE 诱导的心肌肥厚反应并导致肥大消退，这与 CaMKII 活性和钙调神经磷酸酶表达的减少有关。Kv4.3 的表达完全抑制了 NE 诱导的心肌肥厚的发展，并导致肥大心肌的消退。这些作用伴随着 CaMKII 自身磷酸化、PLB 苏氨酸 17 磷酸化的减少，而 PLB 丝氨酸 16 磷酸化没有改变。NFATc3 也被 Kv4.3 的表达所减少。
我们的结果表明，Kv4.3 的减少是通过过度的 CaMKII 激活导致心肌肥厚发展的重要介质，而 Kv4.3 的表达可能是预防和逆转肾上腺素应激诱导的心肌肥厚的潜在治疗策略。
