Section of Cardiology and Center for Cardiovascular Research, University of Illinois at Chicago, 840 S.Wood Street, Chicago, IL 60612, USA.
J Am Coll Cardiol. 2011 Nov 22;58(22):2332-9. doi: 10.1016/j.jacc.2011.07.048.
The aim of this study was to test whether c-Src tyrosine kinase mediates connexin-43 (Cx43) reduction and sudden cardiac death in a transgenic mouse model of cardiac-restricted overexpression of angiotensin-converting enzyme (ACE8/8 mice).
Renin-angiotensin system activation is associated with an increased risk for arrhythmia and sudden cardiac death, but the mechanism is not well understood. The up-regulation of c-Src by angiotensin II may result in the reduction of Cx43, which impairs gap junction function and provides a substrate for arrhythmia.
Wild-type and ACE8/8 mice with and without treatment with the c-Src inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) were studied. Telemetry monitoring, in vivo electrophysiologic studies, Western blot analyses for total and phosphorylated c-Src and Cx43, immunohistochemistry staining for Cx43, and functional assessment of Cx43 with fluorescent dye diffusion were performed.
The majority of the arrhythmic deaths resulted from ventricular tachycardia degenerating to ventricular fibrillation (83%). Levels of total and phosphorylated c-Src were increased and Cx43 reduced in ACE8/8 mice. PP1 reduced total and phosphorylated c-Src levels, increased Cx43 level by 2.1-fold (p < 0.005), increased Cx43 at the gap junctions (immunostaining), improved gap junctional communication (dye spread), and reduced ventricular tachycardia inducibility and sudden cardiac death. The survival rate increased from 11% to 86% with 4 weeks of PP1 treatment (p < 0.005). Treatment with an inactive analog did not change survival or Cx43 levels.
Renin-angiotensin system activation is associated with c-Src up-regulation, Cx43 loss, reduced myocyte coupling, and arrhythmic sudden death, which can be prevented by c-Src inhibition. This suggests that an increase in c-Src activity may help mediate renin-angiotensin system-induced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity.
本研究旨在探讨 c-Src 酪氨酸激酶是否介导心脏特异性过表达血管紧张素转换酶（ACE8/8 小鼠）的转基因小鼠模型中心房连接蛋白 43（Cx43）减少和心源性猝死。
肾素-血管紧张素系统激活与心律失常和心源性猝死风险增加有关，但机制尚不清楚。血管紧张素 II 可使 c-Src 上调，导致 Cx43 减少，从而损害缝隙连接功能并为心律失常提供底物。
研究了野生型和 ACE8/8 小鼠，以及用 c-Src 抑制剂 1-(1,1-二乙基丙基)-1-(4-甲基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺（PP1）治疗的 ACE8/8 小鼠。进行遥测监测、体内电生理研究、总磷酸化 c-Src 和 Cx43 的 Western blot 分析、Cx43 的免疫组织化学染色以及用荧光染料扩散评估 Cx43 的功能。
大多数心律失常性死亡是由室性心动过速发展为心室颤动引起的（83%）。ACE8/8 小鼠的总磷酸化 c-Src 和 Cx43 水平增加，PP1 降低总磷酸化 c-Src 水平，使 Cx43 水平增加 2.1 倍（p < 0.005），增加间隙连接处的 Cx43（免疫染色），改善缝隙连接通讯（染料扩散），减少室性心动过速诱导性和心源性猝死。用 PP1 治疗 4 周后，存活率从 11%增加到 86%（p < 0.005）。用无活性类似物治疗不会改变存活率或 Cx43 水平。
肾素-血管紧张素系统激活与 c-Src 上调、Cx43 缺失、心肌细胞偶联减少和心律失常性心源性猝死有关，c-Src 抑制可预防这种情况。这表明 c-Src 活性增加可能有助于介导肾素-血管紧张素系统引起的心律失常，并且 c-Src 抑制剂可能具有抗心律失常活性。
