Gap junction remodeling and altered connexin43 expression in the failing human heart
Gap junction remodeling and altered connexin43 expression in the failing human heart
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DOI：
10.1023/a:1021154115673
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发表时间：
2003-01-01
影响因子：
4.3
通讯作者：
Schaper, J
中科院分区：
文献类型：
--
作者：
Kostin, S;Rieger, M;Schaper, J
间隙连接（GJ）是心脏传导的重要决定因素，最近有证据表明，这些连接分布的改变及其组成连接蛋白（Cx）表达的变化可能导致心肌细胞之间的异常偶联，并可能导致心律失常。然而，主要心脏GJ蛋白Cx43的表达和分布的变化是多种慢性心肌疾病的普遍特征还是局限于某些特定的病理生理环境，这在很大程度上是未知的。因此，在本研究中，我们开始定性和定量地研究Cx43在正常人心肌和扩张型（DCM）、缺血性（ICM）和炎症性心肌病（MYO）患者中的分布和表达。取心脏移植时左心室组织标本，用免疫共聚焦和电镜观察。与对照组相比，愈合心肌梗死（ICM）、小范围替代纤维化（DCM）和心肌炎症（MYO）边缘肌细胞中的Cx43标记被高度破坏，而不是局限于间盘。在所有组中，远离这些区域的心肌在间盘处显示明显正常的Cx43分布。定量免疫共聚焦分析显示，与正常人心肌相比，DCM心肌的Cx43面积/肌细胞面积或每肌细胞体积分别显著减少30%和55%，ICM心肌的Cx43面积和体积分别减少23%和48%，MYO心肌的Cx43面积和体积分别减少21%和40%。综上所述，GJ分布的局灶性紊乱和Cx43的下调是心肌重构的典型特征，可能在人心肌病致心律失常底物的形成中起重要作用。
Gap junctions (GJ) are important determinants of cardiac conduction and the evidence has recently emerged that altered distribution of these junctions and changes in the expression of their constituent connexins (Cx) may lead to abnormal coupling between cardiomyocytes and likely contribute to arrhythmogenesis. However, it is largely unknown whether changes in the expression and distribution of the major cardiac GJ protein, Cx43, is a general feature of diverse chronic myocardial diseases or is confined to some particular pathophysiological settings. In the present study, we therefore set out to investigate qualitatively and quantitatively the distribution and expression of Cx43 in normal human myocardium and in patients with dilated (DCM), ischemic (ICM), and inflammatory cardiomyopathies (MYO). Left ventricular tissue samples were obtained at the time of cardiac transplantation and investigated with immunoconfocal and electron microscopy. As compared with the control group, Cx43 labeling in myocytes bordering regions of healed myocardial infarction (ICM), small areas of replacement fibrosis (DCM) and myocardial inflammation (MYO) was found to be highly disrupted instead of being confined to the intercalated discs. In all groups, myocardium distant from these regions showed an apparently normal Cx43 distribution at the intercalated discs. Quantitative immunoconfocal analysis of Cx43 in the latter myocytes revealed that the Cx43 area per myocyte area or per myocyte volume is significantly decreased by respectively 30 and 55% in DCM, 23 and 48% in ICM, and by 21 and 40% in MYO as compared with normal human myocardium. In conclusion, focal disorganization of GJ distribution and down-regulation of Cx43 are typical features of myocardial remodeling that may play an important role in the development of an arrhythmogenic substrate in human cardiomyopathies.