Ruan Hongmei, Mitchell Scherise, Vainoriene Monika, Lou Qing, Xie Lai-Hua, Ren Shuxun, Goldhaber Joshua I, Wang Yibin
Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Circulation. 2007 Aug 7;116(6):596-605. doi: 10.1161/CIRCULATIONAHA.106.682773. Epub 2007 Jul 23.
Cardiac hypertrophy is a major risk factor for arrhythmias and sudden cardiac death. However, the underlying signaling mechanisms involved in the induction of arrhythmia and electrophysiological remodeling in cardiac hypertrophy are unclear.
Using an inducible gene-switch approach, we achieved tissue-specific and temporally regulated induction of a well-established hypertrophic pathway, the Ras-Raf-mitogen-activated protein kinases pathway, in adult mouse heart. On Ras activation, the transgenic animal developed ventricular hypertrophy and arrhythmias. The development of ventricular arrhythmias was temporally correlated with electrophysiological remodeling in isolated ventricular myocytes, including action potential prolongation, increased sodium-calcium exchanger activity, reduced outward potassium currents, sarcoplasmic reticulum Ca2+ defects, and loss of protein kinase A-dependent phospholamban phosphorylation. From genome-wide expression profiling, we discovered a selective induction of G alpha inhibiting subunit 1 (Gi alpha1) expression in the Ras transgenic heart. Treatment of transgenic animals with the Gi/o inhibitor pertussis toxin normalized the phospholamban phosphorylation by protein kinase A, reversed the action potential prolongation, and significantly reduced the frequency of cardiac arrhythmias in Ras transgenic animals.
These data suggest that selective induction of G alpha inhibiting subunit 1 expression and activity is a novel downstream event in hypertrophic signaling that may be a critical factor leading to cellular electrophysiological remodeling and cardiac arrhythmias in hypertrophic cardiomyopathy.
心脏肥大是心律失常和心源性猝死的主要危险因素。然而，心脏肥大中诱导心律失常和电生理重塑的潜在信号机制尚不清楚。
使用可诱导基因开关方法，我们在成年小鼠心脏中实现了组织特异性和时间调控的一种成熟肥大途径（Ras-Raf-丝裂原活化蛋白激酶途径）的诱导。Ras激活后，转基因动物出现心室肥大和心律失常。室性心律失常的发生与离体心室肌细胞的电生理重塑在时间上相关，包括动作电位延长、钠钙交换体活性增加、外向钾电流减少、肌浆网Ca2+缺陷以及蛋白激酶A依赖性受磷蛋白磷酸化丧失。通过全基因组表达谱分析，我们发现Ras转基因心脏中Gα抑制亚基1（Giα1）表达有选择性诱导。用Gi/o抑制剂百日咳毒素处理转基因动物可使蛋白激酶A介导的受磷蛋白磷酸化恢复正常，逆转动作电位延长，并显著降低Ras转基因动物的心律失常频率。
这些数据表明，Gα抑制亚基1表达和活性的选择性诱导是肥大信号传导中的一个新的下游事件，可能是导致肥厚型心肌病细胞电生理重塑和心律失常的关键因素。
