Calcineurin在心衰小鼠左心室跨壁电压依赖性钾电流下调中的作用

Role of calcineurin in down-regulation of left ventricular transmural voltagedependent K^+ currents in mice with heart failure

本文旨在探讨钙调神经磷酸酶(calcineurin,Ca N)在心衰心脏左室跨壁电压依赖性钾电流下调中的作用及意义。主动脉弓部分结扎法制备小鼠压力超负荷心衰模型,采用全细胞膜片钳技术,记录应用Ca N抑制剂环孢素A(cyclosporine A,Cs A)后,假手术或心衰小鼠心室肌内膜下(subendocardial,Endo)、外膜下(subepicardial,Epi)心肌细胞电压依赖性钾电流各种成分及动作电位(action potential,AP)的变化。结果显示:各组小鼠左室游离壁心肌细胞的Ca N活性存在明显区域性差异,Endo细胞Ca N活性均高于Epi。心衰时Endo、Epi细胞Ca N活性明显升高,而使用Cs A后Ca N活性降低。在心衰模型小鼠上,Cs A可部分逆转Ito密度的下调,完全逆转Endo和Epi细胞IK,slow密度的下调,完全逆转Endo细胞Iss密度的下调。Cs A可部分逆转心衰小鼠心室肌细胞动作电位时程(action potential duration,APD)的延长,使得增高了的AP跨壁复极离散度(transmural dispersion of repolarization,TDR)明显降低,Endo、Epi细胞APD90的比值由心衰时的4.8:1恢复到2.6:1。以上结果提示,心衰时Endo、Epi细胞Ca N不同程度的激活是电压依赖性钾电流非同步下调,AP的TDR增大的重要原因,抑制Ca N可望成为防治心衰心律失常和猝死的新策略。

The aim of the present study was to investigate the role of calcineurin in the down-regulation of left ventricular transmural voltage-dependent K^＋ currents in heart failure. Transverse aorta was banded by using microsurgical techniques to create mouse heart failure model. Sham-operated （Sham） or aorta banded （Band） mice were randomized to receive calcineurin inhibitor cyclosporine A （CsA） or vehicle. The densities and kinetic properties of voltage-dependent K^＋ currents, as well as action potential （AP）, of left ventricular subendocardial （Endo） and subepicardial （Epi） myocytes were determined by using whole-cell patch-clamp technique. The results showed that calcineurin activity was significant higher in Endo myocytes than that in Epi ones in all the groups. Compared with Sham group, Band mice showed significantly increased calcineurin activity both in Endo and Epi myocytes. CsA significantly reduced calcineurin activity in Band mice. CsA treatment in Band mice partially reversed the down-regulation of Ito density, completely reversed the down-regulation of IK,slow density both in Endo and Epi myocytes, and Iss density in Endo myocytes. In addition, CsA treatment in Band mice partially antagonized the prolongation of action potential duration （APD）, and APD at 50% （APD50） and 90% repolarization （APD90） were significantly reduced. Because of non-parallel shortening of APD in Endo and Epi myocytes, the ratio of Endo/Epi APD90 was reduced from 4.8：1 in Band mice to 2.6：1 in CsA-treated mice, which was close to that in Sham mice. The results suggest that non-parallel activation of calcineurin in Endo and Epi myocytes contributes to the down-regulation of transmural voltage-dependent K^＋ currents and the amplification of transmural dispersion of repolarization （TDR） in left ventricular failure hearts. Inhibition of calcineurin may be a potential new therapeutic strategy to prevent and cure arrhythmias and sudden death in heart failure.