心脏缝隙连接蛋白Cx45的过度表达增加体内室性快速性心律失常的易感性
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Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo
背景与目的
在衰竭的心脏中，涉及缝隙连接的电生理重塑已经被证实，并且可能导致细胞间解耦联、延迟传导、增强心律失常和心力衰竭患者猝死易感性。最近，我们发现，除了以前文献记载的联接蛋白43(Cx 43)表达减少之外，人类心脏衰竭时，连接蛋白45(Cx 45)的表达也明显增加。两者的变化都会导致间隙连接耦联的减少。本研究的目的是研究心脏间隙连接Cx 45的增加所造成的功能影响。
方 法
采用心脏发育中下调的心肌连接蛋白Cx 45选择性过度表达的转基因鼠(Cx45OE小鼠)进行体内电生理研究，采用心内导管诱导麻醉小鼠的心室心律失常。动态心电图监测法检测未麻醉小鼠的自发性心律失常。应用TaqmanRT-PCR、免疫染色、免疫印迹和超声心动图对心脏进行分析。采用荧光黄和神经生物染料转移检测转基因细胞的偶联和控制心肌细胞的培养。
结 果
Cx45mRNA在Cx45OE小鼠中两倍地增加。缝隙连接处的Cx 45免疫反应信号增加了2倍。免疫印迹法检测Cx45OE小鼠与非转基因对照组比较，Cx 45总蛋白含量增加25%。在功能上，Cx45OE小鼠表现出比对照组更易诱导的室性心动过速，但超声心动图评估没有表现出任何其他功能或结构紊乱。从Cx45OE小鼠分离的心室肌细胞表现为减少的细胞间荧光黄染料转移，增加的细胞间神经生物素转移，与细胞间通讯改变一致。
结 论
因此，在体内，Cx45在心肌表达的增加导致细胞间偶联的重构和对室性心律失常更大的易感性。
原始文献摘要
Betsuyaku, Tetsuo, Nkiruka S. Nnebe, Rune Sundset, Sushmitha Patibandla,CharlesM.Krueger,andKathrynA.Yamada.Overexpres-sion of cardiac connexin45 increases susceptibility to ventricular tachyar-rhythmiasinvivo.AmJPhysiolHeartCircPhysiol290:H163–H171,2006.First published August 26, 2005; doi:10.1152/ajpheart.01308.2004.
Abstract
Electrophysiological remodeling involving gap junctions has been demonstrated in failing hearts and may contribute to intercellular uncoupling, delayed conduction, enhanced arrhythmias, and vulnerability to sudden death in patients with heart failure. Recently, we showed that failing human hearts exhibit marked increases in connexin45 (Cx45) expression in addition to previously documented decreases in connexin43 (Cx43) expression. Each of these changes results in reduced gap junction coupling. The objective of the present study was to examine functional consequences of increased Cx45 in cardiac gap junctions. Transgenic mice with cardiac-selective overexpression of the developmentally downregulated cardiac connexin, connexin45 (Cx45OE mice) were subjected to in vivo electrophysiology studies in which an intracardiac catheter was used to induce ventricular arrhythmias in anesthetized mice, and in which ambulatory ECG monitoring was used to detect spontaneous arrhythmias in unanesthetized mice.Hearts were analyzed by TaqMan RT-PCR, immunostaining, immunoblotting, and echocardiography. Lucifer yellow and neurobiotin dye transfer was used to assess coupling in transgenic and control myocyte cultures. Cx45 mRNA was two orders of magnitude greater in Cx45OE mice. Cx45-immunoreactive signal at gap junctions increased twofold and total Cx45 protein by immunoblotting increased 25% in Cx45OE mice compared with nontransgenic littermate controls. Functionally, Cx45OE mice exhibited more inducible ventricular tachycardia than controls but did not exhibit any other functional or structural derangements as assessed by echocardiography. Ventricular myocytes isolated from Cx45OE mice exhibited diminished intercellular transfer of Lucifer yellow dye and increased transfer of neurobiotin, consistent with altered cell-to-cell communication. Thus increased myocardial expression of Cx45 results in remodeling of intercellular coupling and greater susceptibility to ventricular arrhythmias in vivo.
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