Cardiovascular Research Center, Mount Sinai School of Medicine, Atran Building AB5-10, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA.
J Mol Cell Cardiol. 2010 Jun;48(6):1169-79. doi: 10.1016/j.yjmcc.2009.12.019. Epub 2010 Jan 4.
Recent evidence shows that the auxiliary subunit KChIP2, which assembles with pore-forming Kv4-subunits, represents a new potential regulator of the cardiac calcium-independent transient outward potassium current (I(to)) density. In hypertrophy and heart failure, KChIP2 expression has been found to be significantly decreased. Our aim was to examine the role of KChIP2 in cardiac hypertrophy and the effect of restoring its expression on electrical remodeling and cardiac mechanical function using a combination of molecular, biochemical and gene targeting approaches. KChIP2 overexpression through gene transfer of Ad.KChIP2 in neonatal cardiomyocytes resulted in a significant increase in I(to)-channel forming Kv4.2 and Kv4.3 protein levels. In vivo gene transfer of KChIP2 in aortic banded adult rats showed that, compared to sham-operated or Ad.beta-gal-transduced hearts, KChIP2 significantly attenuated the developed left ventricular hypertrophy, robustly increased I(to) densities, shortened action potential duration, and significantly altered myocyte mechanics by shortening contraction amplitudes and maximal rates of contraction and relaxation velocities and decreasing Ca(2+) transients. Interestingly, blocking I(to) with 4-aminopyridine in KChIP2-overexpressing adult cardiomyocytes significantly increased the Ca(2+) transients to control levels. One-day-old rat pups intracardially transduced with KChIP2 for two months then subjected to aortic banding for 6-8 weeks (to induce hypertrophy) showed similar echocardiographic, electrical and mechanical remodeling parameters. In addition, in cultured adult cardiomyocytes, KChIP2 overexpression increased the expression of Ca(2+)-ATPase (SERCA2a) and sodium calcium exchanger but had no effect on ryanodine receptor 2 or phospholamban expression. In neonatal myocytes, KChIP2 notably reversed Ang II-induced hypertrophic changes in protein synthesis and MAP-kinase activation. It also significantly decreased calcineurin expression, NFATc1 expression and nuclear translocation and its downstream target, MCiP1.4. Altogether, these data show that KChIP2 can attenuate cardiac hypertrophy possibly through modulation of intracellular calcium concentration and calcineurin/NFAT pathway.
最近的证据表明，辅助亚基 KChIP2 与形成孔的 Kv4 亚基组装，代表了心脏钙非依赖性瞬态外向钾电流（I(to)）密度的新的潜在调节剂。在肥大和心力衰竭中，已经发现 KChIP2 的表达显著降低。我们的目的是通过分子、生化和基因靶向方法的结合，研究 KChIP2 在心脏肥大中的作用，以及恢复其表达对电重构和心脏机械功能的影响。通过 Ad.KChIP2 的基因转移在乳鼠心肌细胞中过表达 KChIP2，导致 I(to)通道形成 Kv4.2 和 Kv4.3 蛋白水平显著增加。在主动脉缩窄成年大鼠中的体内基因转移显示，与假手术或 Ad.beta-gal 转导的心脏相比，KChIP2 显著减弱了已发展的左心室肥大，强烈增加了 I(to)密度，缩短了动作电位持续时间，并通过缩短收缩幅度和最大收缩和松弛速度以及降低 Ca(2+)瞬变来显著改变心肌力学。有趣的是，在过表达 KChIP2 的成年心肌细胞中用 4-氨基吡啶阻断 I(to)可将 Ca(2+)瞬变显著增加至对照水平。通过心内转导 KChIP2 两个月然后接受主动脉缩窄 6-8 周（诱导肥大）的 1 天大的大鼠幼仔显示出类似的超声心动图、电和机械重构参数。此外，在培养的成年心肌细胞中，KChIP2 的过表达增加了 Ca(2+)-ATPase（SERCA2a）和钠钙交换体的表达，但对肌浆网 Ca(2+)释放通道 2a 或肌球蛋白轻链磷酸酶表达没有影响。在乳鼠心肌细胞中，KChIP2 显著逆转了 Ang II 诱导的蛋白质合成和 MAP 激酶激活的肥大变化。它还显著降低了钙调神经磷酸酶表达、NFATc1 表达和核易位及其下游靶标，MCiP1.4。总的来说，这些数据表明 KChIP2 可以通过调节细胞内 Ca(2+)浓度和钙调神经磷酸酶/NFAT 途径来减轻心脏肥大。
