Inflammasome mediated pathogenesis of atrial fibrillation

 说明(申请人提供)：房颤(房颤)是最常见的心律失常，患病率不断增加，并与显著的发病率、死亡率和社会经济负担有关。了解房颤发生的分子机制，评估房颤干预的新靶点具有重要意义。无菌炎症是房颤患者的病理生理改变之一，炎症标志物水平可以预测房颤消融的成功与否。例如，持续性和永久性房颤患者的IL-1β水平升高，与窦性心律相反。据推测，持续性房颤可能诱导炎症反应，导致细胞因子的释放，进而可能触发成纤维细胞分化为肌成纤维细胞以及 离子通道功能障碍。这些事件，连同心肌细胞凋亡和异常细胞外基质的产生和更新，可能都有助于房颤患者的电学和结构重构。尽管炎症反应增强与房颤持续存在明显联系，但房颤患者IL-1β水平升高的分子机制尚未被研究。已知‘NACHT、LRR和PYD结构域包含蛋白3’(NLRP3)炎症体介导IL-1β的成熟。我们的初步研究表明，NLRP3炎症体在CREM转基因小鼠中上调，这是一种自发性房颤的小鼠模型。慢性心力衰竭小鼠房颤的发生与纤维化增加和心房增大有关，而IL-1β可加重房颤的发生。另一方面，我们还发现，与对照组小鼠相比，心脏表达Nlrp3基因A350V突变的小鼠更容易发生起搏诱发的房颤；而Nlrp3缺陷小鼠(Nlrp3-/-)则对房颤诱导具有抵抗力。因此，我们将测试总体假设，即增强的激活 NLRP3炎症体通过细胞凋亡和纤维化重塑促进房颤的发生。我们建议1)建立NLRP3炎性小体激活与房颤发生之间的因果关系，2)阐明NLRP3炎性小体激活促进房颤发生的机制，3)评价NLRP3炎性小体抑制在房颤干预中的治疗潜力。我们的结果可以迅速转化为临床实践。这些实验结果将为房颤的药物干预开辟新的领域。

 DESCRIPTION (provided by applicant): Atrial Fibrillation (AF) is the most prevalent arrhythmia with an increasing prevalence and associated with pronounced morbidity, mortality, and socioeconomic burden. It is of great interest to understand the molecular mechanisms of AF development and to evaluate novel targets for AF intervention. Sterile inflammation is one of the pathophysiological changes found in AF patients, and levels of inflammation markers can predict the successful outcome of AF ablation. For example, the interleukin (IL)-1β level is increased in patients with persistent and permanent AF, in contrast to sinus rhythm. It has been postulated that the sustained AF may induce an inflammatory response leading to the release of cytokines, which in turn may trigger both fibroblast differentiation into myofibroblasts as well as ion channel dysfunction. These events, along with myocyte apoptosis and abnormal extracellular matrix generation and turnover, likely contribute to both the electrical and structurl remodeling seen in AF patients. Despite the obvious link between enhanced inflammatory response and AF perpetuation, the molecular mechanism underlying the increased level of IL-1β in AF has not been investigated. It is known that `NACHT, LRR and PYD domains-containing protein 3' (NLRP3) inflammasome mediates the maturation of IL-1β. Our preliminary study has revealed that NLRP3 inflammasome is upregulated in CREM transgenic mice, a mouse model spontaneous AF. AF development in CREM mice is associated with increased fibrosis and atrial enlargement, which could be exacerbated by IL-1β. On the other hand, we also found that mice with cardiac expression of constitutively active A350V mutation of Nlrp3 are more susceptible to pacing-induced AF; whereas Nlrp3 deficient mice (Nlrp3-/-) are resistant to AF induction, in contrast to control mice. Thus, we will test the overall hypothesis that the enhanced activation of the NLRP3 inflammasome promotes AF by apoptotic and fibrotic remodeling. We propose to 1) establish the causal association between NLRP3 inflammasome activation and AF development, 2) elucidate the mechanisms by which activation of the NLRP3 inflammasome promotes AF, and 3) evaluate the therapeutic potential of NLRP3 inflammasome inhibition in AF intervention. Our results could be rapidly translated into clinical practice. The results from thes proposed experiments would open up a new area for novel pharmacologic intervention in AF.