Chen Xue, Bai Yan, Sun Hanqi, Su Zhenli, Guo Jing, Sun Chuan, Du Zhimin
Institute of Clinical Pharmacy, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, China.
Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.
Cell Physiol Biochem. 2017;43(3):915-925. doi: 10.1159/000481642. Epub 2017 Sep 29.
BACKGROUND/AIMS: Cardiac hypertrophy (CH) is an adaptive response to diverse cardiovascular conditions, which is accompanied by adverse electrical remodeling manifested as abnormal K+ channel activities. M3 subtype of muscarinic acetylcholine receptor (M3-mAChR) is a novel regulator of cardiac electrical activity. In this study we aim to explore if the overexpression of M3-mAChR could attenuate the adverse electrical remodeling in CH and then uncover its underlying electrophysiological mechanisms.
Transgenic mice with M3-mAChR overexpression (M3-TG) and wild type (WT) mice were subjected to transverse aortic constriction (TAC) to induce CH. Myocardial hypertrophy and cardiac function were quantified by the measurement of echocardiography, electrocardiogram, heart weight and tibia length. Whole-cell and signal-cell patch-clamp were employed to record electrophysiological properties by acute isolation of acutely isolated ventricular cardiomyocytes and Western blot was carried out to evaluate the Kir2.1and Kv4.2/4.3 protein levels in left ventricular tissue.
Compared with WT group, the elevation of cardiac index, including heart weight/body weight index and heart weight/tibia length index confirmed the myocardial hypertrophic growth induced by TAC. Echocardiography detection revealed that the TAC-treated mice showed an obvious increase in the thickness of left ventricular posterior wall (LVPW) and ejection fraction (EF) due to compensatory hypertrophy, which attenuated by the overexpression of M3-mAChR. Pressure overload induced a prolongation of QTc interval in WT mice, an effect blunted in M3-TG mice. Furthermore, compared with WT mice, M3-mAChR overexpression in hypertrophic myocardium accelerated cardiac repolarization and shortened action potential duration, and thus correcting the prolongation of QTc interval. Moreover, M3-TG mice have the greater current density of IK1 and Ito in ventricular myocytes after TAC compared with WT mice. Finally, compared with WT mice, M3-TG mice expressed higher levels of Kir2.1 in ventricular myocytes.
M3-mAChR overexpression protected against adverse electrical remodeling in CH by enhancing potassium currents and promoting repolarization.
背景/目的：心肌肥厚（CH）是对多种心血管疾病的一种适应性反应，它伴随着以异常钾通道活动为表现的不良电重构。毒蕈碱型乙酰胆碱受体M3亚型（M3-mAChR）是心脏电活动的一种新型调节因子。在本研究中，我们旨在探讨M3-mAChR的过表达是否能减轻CH中的不良电重构，进而揭示其潜在的电生理机制。
将M3-mAChR过表达的转基因小鼠（M3-TG）和野生型（WT）小鼠进行主动脉缩窄（TAC）以诱导CH。通过超声心动图、心电图、心脏重量和胫骨长度的测量来量化心肌肥厚和心脏功能。采用全细胞和单细胞膜片钳技术，通过急性分离心室心肌细胞记录电生理特性，并进行蛋白质免疫印迹法评估左心室组织中Kir2.1和Kv4.2/4.3蛋白水平。
与WT组相比，心脏指数的升高，包括心脏重量/体重指数和心脏重量/胫骨长度指数，证实了TAC诱导的心肌肥厚性生长。超声心动图检测显示，TAC处理的小鼠由于代偿性肥厚，左心室后壁厚度（LVPW）和射血分数（EF）明显增加，而M3-mAChR的过表达减弱了这种增加。压力超负荷导致WT小鼠QTc间期延长，而在M3-TG小鼠中这种效应减弱。此外，与WT小鼠相比，肥厚心肌中M3-mAChR的过表达加速了心脏复极化并缩短了动作电位时程，从而纠正了QTc间期的延长。而且，与WT小鼠相比，TAC后M3-TG小鼠心室肌细胞中IK1和Ito的电流密度更大。最后，与WT小鼠相比，M3-TG小鼠心室肌细胞中Kir2.1表达水平更高。
M3-mAChR的过表达通过增强钾电流和促进复极化来保护CH中的不良电重构。
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