Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1.
Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1.
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DOI：
10.1093/cvr/cvm083
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发表时间：
2008-03-01
影响因子：
10.8
通讯作者：
Severs NJ
中科院分区：
文献类型：
--
作者：
Bruce AF;Rothery S;Dupont E;Severs NJ
间隙连接的重构，包括总间隙连接数量的减少和连接蛋白43（Cx43）的下调，有助于充血性心力衰竭的代谢底物。然而，对潜在的机制知之甚少。最近的研究表明，在体外系统的连接蛋白相互作用蛋白zonula occludens-1（ZO-1）是一个潜在的介导的间隙连接重塑。因此，我们研究的假设，ZO-1有助于减少表达的Cx43缝隙连接在充血性心力衰竭。将来自健康对照人类心脏（n = 5）的左心室心肌与来自患有由于特发性扩张型心肌病（DCM; n = 5）或缺血性心肌病（ICM; n = 5）的终末期充血性心力衰竭的移植患者的心脏的左心室心肌进行比较。免疫共聚焦和免疫电镜显示ZO-1特异性定位于对照组和衰竭组心肌细胞的闰盘。ZO-1蛋白水平在DCM和ICM中均显著增加（P = 0.0025），显示与Cx43水平显著负相关（P = 0.0029）。ZO-1 mRNA表达无明显变化（P = 0.537）。双免疫标记表明，ZO-1标记的比例与Cx43共定位，并且Cx43与ZO-1的共定位在衰竭心室中显著增加（P = 0.003）。通过免疫共沉淀证实了两种蛋白质之间的相互作用。Cx43与ZO-1共免疫沉淀的比例在衰竭心脏中显著增加。我们的研究结果表明，ZO-1，通过与Cx43相互作用，在下调和减少充血性心力衰竭的Cx43缝隙连接的大小中发挥作用。
Remodelling of gap junctions, involving reduction of total gap junction quantity and down-regulation of connexin43 (Cx43), contributes to the arrhythmic substrate in congestive heart failure. However, little is known of the underlying mechanisms. Recent studies from in vitro systems suggest that the connexin-interacting protein zonula occludens-1 (ZO-1) is a potential mediator of gap junction remodelling. We therefore examined the hypothesis that ZO-1 contributes to reduced expression of Cx43 gap junctions in congestive heart failure. Left ventricular myocardium from healthy control human hearts (n = 5) was compared with that of explanted hearts from transplant patients with end-stage congestive heart failure due to idiopathic dilated cardiomyopathy (DCM; n = 5) or ischaemic cardiomyopathy (ICM; n = 5). Immunoconfocal and immunoelectron microscopy showed that ZO-1 is specifically localized to the intercalated disc of cardiomyocytes in control and failing ventricles. ZO-1 protein levels were significantly increased in both DCM and ICM (P = 0.0025), showing a significant, negative correlation to Cx43 levels (P = 0.0029). There was, however, no significant alteration of ZO-1 mRNA (P = 0.537). Double immunolabelling demonstrated that a proportion of ZO-1 label is co-localized with Cx43, and that co-localization of Cx43 with ZO-1 is significantly increased in the failing ventricle (P = 0.003). Interaction between the two proteins was confirmed by co-immunoprecipitation. The proportion of Cx43 that co-immunoprecipitates with ZO-1 was significantly increased in the failing heart. Our findings suggest that ZO-1, by interacting with Cx43, plays a role in the down-regulation and decreased size of Cx43 gap junctions in congestive heart failure.