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（由适用提供）：心房颤动（AF）是最普遍的心律失常，患病率越来越高，与明显的发病率，死亡率和社会经济伯恩（Burnen）有关。了解AF发育的分子机制并评估AF干预的新目标是非常有趣的。无菌炎症是AF患者发现的病理生理变化之一，炎症标志物水平可以预测AF消融的成功结果。例如，与窦性节奏相比，持续和永久性AF的患者的白介素（IL）-1β水平升高。据推测，持续的AF可能引起炎症反应，导致细胞因子释放，进而触发成纤维细胞分化为肌纤维细胞以及 离子通道功能障碍。这些事件以及心肌细胞凋亡以及异常的细胞外基质产生和营业额，可能有助于AF患者看到的电气和结构重塑。尽管炎症反应增强与AF持续性之间存在明显的联系，但尚未研究AF中IL-1β水平升高的分子机制。众所周知，含有含蛋白质的NACHT，LRR和PYD结构域3'（NLRP3）炎性体介导IL-1β的成熟。我们的初步研究表明，NLRP3炎性体在CREM转基因小鼠（一种鼠标模型的赞助AF）中进行了更新。 CREM小鼠的AF发育与纤维化增加和心房增强有关，这可能会因IL-1β而加剧。另一方面，我们还发现，NLRP3组成型活性A350V突变的心脏表达的小鼠更容易受到起搏诱导的AF。与对照小鼠相比，NLRP3缺陷小鼠（NLRP3 - / - ）对AF诱导具有抵抗力。这，我们将测试总体假设，即增强的激活 NLRP3炎性体通过凋亡和纤维化重塑促进AF。我们建议1）建立NLRP3炎症体激活与AF发育之间的因果关系，2）阐明NLRP3炎性体的激活促进AF的机制，以及3）评估NLRP3炎性症在AF干预下抑制NLRP3炎性症的治疗潜力。我们的结果可以迅速转化为临床实践。提出的实验的结果将为AF中的新药理干预开辟一个新领域。