Cardiac β-adrenergic receptor activation mediates distinct and cell type-dependent changes in the expression and distribution of connexin 43
Cardiac β-adrenergic receptor activation mediates distinct and cell type-dependent changes in the expression and distribution of connexin 43
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心脏 β-肾上腺素能受体激活介导连接蛋白 43 的表达和分布的独特和细胞类型依赖性变化。
DOI：
10.1111/jcmm.15469
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Xiaojun Du
中科院分区：
文献类型：
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作者：
Yi Zhang;Mengchen Hou;Jingjing Li;Ying Qi;Yu Zhang;Gang She;Yujie Ren;Wei Wu;Zhengda Pang;Wenjun Xie;Xiuling Deng;Xiaojun Du
交感神经-β-肾上腺素能受体（β-AR）系统的激活是心力衰竭的标志，导致纤维化和心律失常。连接蛋白43（Cx43）是心肌中含量最丰富的间隙连接蛋白。目前的知识是有限的，关于Cx43重塑在不同类型的细胞在患病的心肌和潜在的机制。我们研究了由于β-AR过度激活引起的Cx43重构的细胞类型依赖性变化及其分子机制。使用异丙肾上腺素刺激或β2-AR转基因心肌细胞过表达的小鼠模型，其表现出心脏纤维化和上调的总Cx43丰度。在这两种模型中，而心肌细胞中的Cx43表达减少，更横向分布，成纤维细胞表现出Cx43表达升高，增强间隙连接通讯。从机制上讲，体外成纤维细胞中β2-AR的激活会增加Cx43的表达，这可以被β2-拮抗剂ICI-118551或蛋白激酶A抑制剂H-89消除，但可以被腺苷酸环化酶激活剂forskolin模拟。我们的体外和体内数据表明，β-AR激活诱导的IL-18产生以旁分泌方式依次刺激成纤维细胞中的Cx43表达。总之，我们的研究结果表明，β-AR在介导Cx43表达和分布的独特和细胞类型依赖性变化中发挥关键作用，导致心肌中的病理性间隙连接重塑。
Activation of the sympatho‐β‐adrenergic receptors (β‐ARs) system is a hallmark of heart failure, leading to fibrosis and arrhythmias. Connexin 43 (Cx43) is the most abundant gap junctional protein in the myocardium. Current knowledge is limited regarding Cx43 remodelling in diverse cell types in the diseased myocardium and the underlying mechanism. We studied cell type‐dependent changes in Cx43 remodelling due to β‐AR overactivation and molecular mechanisms involved. Mouse models of isoproterenol stimulation or transgenic cardiomyocyte overexpression of β2‐AR were used, which exhibited cardiac fibrosis and up‐regulated total Cx43 abundance. In both models, whereas Cx43 expression in cardiomyocytes was reduced and more laterally distributed, fibroblasts exhibited elevated Cx43 expression and enhanced gap junction communication. Mechanistically, activation of β2‐AR in fibroblasts in vitro elevated Cx43 expression, which was abolished by the β2‐antagonist ICI‐118551 or protein kinase A inhibitor H‐89, but simulated by the adenylyl cyclase activator forskolin. Our in vitro and in vivo data showed that β‐AR activation‐induced production of IL‐18 sequentially stimulated Cx43 expression in fibroblasts in a paracrine fashion. In summary, our findings demonstrate a pivotal role of β‐AR in mediating distinct and cell type‐dependent changes in the expression and distribution of Cx43, leading to pathological gap junction remodelling in the myocardium.