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Gap Junction Remodeling and Arrhythmogenesis in Ischemic Heart

缺血性心脏间隙连接重塑和心律失常发生

基本信息

批准号：
16591417
负责人：
KANNO Shigeto
金额：
$ 2.24万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591417/
关键词：
Gap Junction Connexin43 Ischemia Arrhythmia

项目摘要

In Japan sudden cardiac death is common in patients who have survived myocardial infarction. Also many patients who have cardiac dysfunction have the high risk of sudden arrhythmic death. But the molecular mechanisms responsible for the lethal arrhythmia in such patients have not defined yet In order to gain insights about the role of critical arrhythmia we created the ischemia model in mice heterozygous for a major gap junction protein Cx43 null allele and wild type. The structural consequences following myocardial infarction (MI) were examined by echocardiography and histopathological study. Although post-infarction remodeling was not affected by diminished Cx43 expression in cardiac gap junctions, infarct size was smaller it C×43-deficient (C×43+/-) mice compared with wild type (C×43+/+). Implanted telemetry system revealed spontaneous ventricular arrhythmias occurred only in C×43+/-mice with infarction. Isolated hearts with healed myocardial infarction were analyzed by the arrhythm … More ia induction study. Ventricular tachycardia was induced in both Cx43+/-and +/+ hearts with MI. But the inducibility of ventricular arrhythmia was higher in C×43+/-in acute phase in mice with ischemia. Interestingly the electrica recovery was rather quick compared with morphological wound healing. Reduced basal coupling was observed as the distribution of Cx43 in gap junction channel which was visualized by immunohistochemical study. Gap junction remodeling was considered as an essential factor of arrhythmogenesis in heart with ischemic injury. Perioperative patients in human cardiac surgery are considered as being in the similar condition of these ischemic model. Analysis of arrhythmias following MI in mouse lines with defined genetic defects will shed light on the roles of these proteins in sudden cardiac death in patients with healed MI or post operative patients. Alterations in cell-cell communication occur as a fundamental response to myocyte injury which contributes to arrhythmogenesis. Human disease models in genetically altered mice are invaluable for mechanistic understanding of sudder cardiac death and to prevent it at its source instead of terminating a lethal arrhythmia once it occurred. Less

在日本，心脏性猝死在心肌梗死后存活的患者中很常见。此外，许多患有心功能障碍的患者具有猝死的高风险。但是在这些患者中导致致命性心律失常的分子机制尚未确定。为了获得关于严重心律失常的作用的见解，我们在主要间隙连接蛋白Cx43无效等位基因和野生型杂合小鼠中建立了缺血模型。通过超声心动图和组织病理学研究心肌梗死（MI）后的结构后果。虽然心肌梗死后重构不受心肌缝隙连接中Cx43表达减少的影响，但与野生型（C × 43 +/+）小鼠相比，C×43缺陷（C × 43 +/-）小鼠的梗死面积较小。植入的遥测系统显示自发性室性心律失常仅发生在C×43+/-梗死小鼠中。用彩色多普勒超声心动图分析心肌梗死愈合的离体心脏， ...更多信息通过诱导研究。在MI的Cx43+/-和+/+心脏中均诱发室性心动过速。但C×43+/-组在急性缺血期诱发室性心律失常的作用更强。有趣的是，与形态学伤口愈合相比，电恢复相当快。免疫组化观察到缝隙连接通道中Cx43的分布减少。缝隙连接重构被认为是缺血性心脏损伤后发生心肌梗死的重要因素。人类心脏手术中的围手术期患者被认为处于这些缺血模型的类似状况。在具有确定的遗传缺陷的小鼠系中分析MI后的心律失常将阐明这些蛋白质在MI治愈患者或手术后患者的心源性猝死中的作用。细胞间通讯的改变是对肌细胞损伤的一种基本反应，有助于心肌发生。人类疾病模型中的转基因小鼠是非常宝贵的机械理解心脏猝死，并防止它在其源头，而不是终止致命的心律失常一旦发生。少