Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation.
Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation.
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Cadherin-11 缺乏可减轻 Ang-II 诱导的心房纤维化和心房颤动的易感性
DOI：
10.2147/jir.s306073
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发表时间：
2021
影响因子：
4.5
通讯作者：
Wang QS
中科院分区：
文献类型：
--
作者：
Cao W;Song S;Fang G;Li Y;Wang Y;Wang QS
研究背景心房纤维化是心房颤动发生发展的一个始动机制。血管紧张素II（Ang-II）是心房纤维化的关键介质，其异常激活心房成纤维细胞（AF）成为肌成纤维细胞，导致随后细胞外基质（ECM）的过度合成和沉积。钙粘蛋白-11（CDH 11）在非心脏纤维化疾病的发展中是必不可少的。在本研究中，我们探讨了它在心房颤动的发病机制和潜在机制中的作用。方法取心房颤动患者和Ang-II诱导的心房纤维化小鼠的左心房组织。我们利用一个整体CDH 11敲除小鼠（CDH 11 −/-）模型来确定CDH 11对AF细胞增殖、迁移、ECM合成/沉积的影响。对来自CDH 11 −/-或正常小鼠的分离的AF进行RNA-Seq，并分析差异表达的基因。通过心脏电生理检查小鼠对心房颤动的易感性。结果钙粘蛋白-11在房颤患者和Ang-II诱导的小鼠的纤维化心房组织中表达显著上调。正常和CDH 11 −/-小鼠在静息状态下均未发生心房纤维化。然而，在Ang-II输注后，与正常小鼠中发生的严重心房纤维化不同，CDH 11 −/-小鼠显示出减少的心房纤维化。来自CDH 11 −/-小鼠的CDH 11缺失的心房成纤维细胞显示Ang-II诱导的细胞增殖，迁移和ECM合成/沉积减少，表明CDH 11参与心房纤维化。一致地，CDH 11缺失AF的RNA-Seq揭示了促纤维化基因表达的显著降低。此外，我们确定了与Smad 2/3，ERK 1/2和JNK通路相关的转录物的减少。此外，CDH 11 −/-小鼠显示出显著减弱的Ang-II诱导的房颤易感性。结论CDH 11增强Ang-II诱导的AF活化。心房纤维化的发病机制是通过CDH 11介导的Smad 2/3、ERK 1/2和JNK途径的刺激。因此，CDH 11可能作为一种新的治疗靶点，用于改善心房颤动的发展。
Background Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation. Methods We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11−/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11−/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology. Results We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11−/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11−/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11−/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11−/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation. Conclusion Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation.