Inflammasome mediated pathogenesis of atrial fibrillation

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 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.