Danik Stephan B, Liu Fangyu, Zhang Jie, Suk H Jacqueline, Morley Gregory E, Fishman Glenn I, Gutstein David E
The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York 10010, USA.
Circ Res. 2004 Nov 12;95(10):1035-41. doi: 10.1161/01.RES.0000148664.33695.2a. Epub 2004 Oct 21.
Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline ("O-CKO" mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (P<0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias.
连接蛋白43（Cx43）是心室中主要的间隙连接蛋白，对维持正常心脏电传导至关重要，小鼠心脏中缺乏该蛋白会导致突然心律失常死亡。心脏中Cx43丰度降低与恶性室性心律失常的诱导性之间的机制尚未明确。在本报告中，我们研究了一种经过基因工程改造以表达逐渐降低水平的Cx43的小鼠模型的心律失常易感性。将年龄逐渐增大的心脏限制性Cx43条件性敲除（CKO）小鼠进行选择性繁殖，以产生心脏特异性Cx43缺陷亚系（“O-CKO”小鼠），其中心脏中Cx43的缺失更为缓慢。O-CKO小鼠的寿命明显长于最初的CKO小鼠系列，但仍会突然过早死亡。在25日龄时，心脏Cx43蛋白水平降至对照值的59%（P<0.01），但传导速度没有显著降低，且没有O-CKO小鼠可诱发出持续性室性心律失常。到45日龄时，心脏Cx43丰度以异质性方式降至对照水平的18%，传导速度减慢至对照心脏的一半，80%的O-CKO小鼠可诱发出致命性心律失常。对诱发性心律失常的易感性增强与有创血流动力学测量的改变或心室有效不应期的变化无关。因此，Cx43丰度的中度严重降低与冲动传播减慢以及诱发性室性心律失常的易感性显著增加有关。
