Inflammasome mediated pathogenesis of atrial fibrillation

炎症小体介导的房颤发病机制

• 批准号: 9336416
• 负责人: Na Li
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336416
• 关键词: Ablation; Age; Apoptosis; Apoptotic; Area; Arrhythmia; Atrial Fibrillation; Attenuated; Biological Markers; Biopsy; CASP1 gene; Cardiac; Cardiac Myocytes; Cell Death; Cellular Morphology; Dependovirus; Development; Drosophila pros protein; Electrocardiogram; Electrophysiology (science); Enzyme-Linked Immunosorbent Assay; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Generations; Genetic; Glyburide; Goals; Health; Heart Atrium; In Situ Nick-End Labeling; Incidence; Inflammation; Inflammatory Response; Interleukin-1 beta; Intervention; Ion Channel; Link; Maintenance; Maps; Measures; Mediating; Metalloproteases; Molecular; Morbidity - disease rate; Multiprotein Complexes; Mus; Muscle Cells; Mutation; Myofibroblast; Optics; Outcome; Pathogenesis; Patients; Play; Predisposition; Prevalence; Prevention; Production; Proteins; Research; Resistance; Role; Serum; Sinus; Staining method; Stains; Sterility; Telemetry; Testing; Therapeutic; Tissues; Transgenic Mice; Translating; Trichrome stain; Western Blotting; Work; attenuation; base; cell type; cholinergic; clinical practice; cytokine; gene therapy; in vivo; inflammatory marker; inhibitor/antagonist; interest; knock-down; mortality; mouse model; novel; overexpression; prevent; programs; promoter; research study; small hairpin RNA; socioeconomics

 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.

 描述（由申请人提供）：房颤（AF）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相关。了解房颤发生的分子机制和评估房颤干预的新靶点具有重要意义。无菌性炎症是房颤患者的病理生理变化之一，炎症标志物的水平可以预测房颤消融术的成功结局。例如，与窦性心律相比，持续性和永久性AF患者的白细胞介素（IL）-1β水平升高。据推测，持续性AF可诱导炎症反应，导致细胞因子的释放，这进而可触发成纤维细胞分化成肌成纤维细胞以及成纤维细胞的分化。 离子通道功能障碍这些事件，沿着肌细胞凋亡和异常细胞外基质生成和周转，可能有助于AF患者中观察到的电和结构重塑。尽管增强的炎症反应与AF永久化之间存在明显联系，但AF中IL-1β水平升高的分子机制尚未研究。已知含有NACHT、LRR和PYD结构域的蛋白3（NLRP 3）炎性体介导IL-1β的成熟。我们的初步研究已经揭示了NLRP 3炎性体在CREM转基因小鼠（一种自发性AF的小鼠模型）中上调。CREM小鼠中的AF发展与纤维化增加和心房扩大相关，这可能被IL-1β加重。另一方面，我们还发现，心脏表达Nlrp 3的组成型活性A350 V突变的小鼠对起搏诱导的AF更敏感;而与对照小鼠相比，Nlrp 3缺陷小鼠（Nlrp 3-/-）对AF诱导具有抗性。因此，我们将测试总体假设，即增强的激活 NLRP 3炎性体通过凋亡和纤维化重塑促进AF。我们建议1）建立NLRP 3炎性体激活和AF发展之间的因果关系，2）阐明NLRP 3炎性体激活促进AF的机制，3）评估NLRP 3炎性体抑制在AF干预中的治疗潜力。我们的研究结果可以迅速转化为临床实践。这些实验结果将为AF的新型药物干预开辟一个新的领域。