Cardiac fibroblast inflammasome and atrial myopathy

项目总结 房颤是最常见的心律失常。房性肌病是发展的关键决定因素。 自动对讲机。房颤促进性心房肌病演变的分子机制是复杂的和 人们对此知之甚少。包括‘NLR家族3’(NLRP3)在内的先天炎症信号 炎性小体途径可调节心功能和房性心律失常的发生。我们的初步研究 持续性房颤患者心房成纤维细胞中NLRP3炎症体活性增强 患者与窦性心律对照组进行比较。NLRP3在小鼠体内的Cf特异性激活促进 出现心房纤维化，左心房增大，心房收缩能力降低，脉冲传导异常， 窦房结功能障碍和房颤易感性增加，与房颤相关的表现性心房肌病 发展。在这个方案中，我们将检验这样一种假设，即激活CF炎性小体可以增强心房功能 促进房性肌病引起的心律失常。此外，加强治疗的潜力 对抗房肌病和房性心律失常的炎症消退值得评价。在这 我们还将评估消炎诱导剂是否可以预防炎症小体- 诱发房性肌病，从而减少房性心律失常的发生。这项提案涉及几个 房颤发病机制研究不足的领域。这项研究的结果将为研究 房性肌病和窦房结功能障碍的发展，以及使用PRO的理论基础。 房颤预防中的分辨分子。

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Atrial myopathy is a key determinant of the development of AF. The molecular mechanisms underlying the evolution of AF-promoting atrial myopathy are complex and poorly understood. Innate inflammatory signaling including the ‘NLR family pyrin domain containing 3’ (NLRP3) inflammasome pathway can modulate cardiac function and atrial arrhythmogenesis. Our preliminary study revealed that NLRP3 inflammasome activity is enhanced in atrial cardiac fibroblasts (CFs) of persistent AF patients compared with sinus rhythm controls. The CF-specific activation of NLRP3 in mice promotes the development of atrial fibrosis, enlarged left atrium, reduced atrial contractility, abnormal impulse conduction, sinus node dysfunction, and increased AF susceptibility, phenocopying atrial myopathy associated with AF development. In this proposal, we will test the hypothesis that activation of CF inflammasomes enhances atrial arrhythmogenesis by promoting atrial myopathy. Additionally, the therapeutic potential of enhancing the resolution of inflammation to combat atrial myopathy and atrial arrhythmogenesis deserves evaluation. In this proposal, we will also evaluate whether an inducer of inflammation resolution can prevent the inflammasome- induced atrial myopathy, thereby reducing atrial arrhythmogenesis. This proposal addresses several understudied areas in AF pathogenesis. The outcome of this study will provide novel insights into the development of atrial myopathy and sinus node dysfunction, as well as provide rationale for using the pro- resolution molecule in AF prevention.