Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation.
Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation.
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DOI：
10.1161/circulationaha.118.035202
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发表时间：
2018-11-13
期刊：
影响因子：
37.8
通讯作者：
Li N
中科院分区：
文献类型：
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作者：
Yao C;Veleva T;Scott L Jr;Cao S;Li L;Chen G;Jeyabal P;Pan X;Alsina KM;Abu-Taha I Dr;Ghezelbash S;Reynolds CL;Shen YH;LeMaire SA;Schmitz W;Müller FU;El-Armouche A;Tony Eissa N;Beeton C;Nattel S;Wehrens XHT;Dobrev D;Li N
心房颤动（AF）常与炎症反应增强相关。“含NACHT、LRR和PYD结构域的蛋白3”（NLRP 3）-炎性体介导免疫细胞中的半胱天冬酶-1活化和白细胞介素-1 β释放，但不知道在心肌细胞（CM）中发挥作用。在这里，我们评估了CM NLRP 3-炎性体在AF中的作用。通过免疫印迹法评估了来自阵发性（pAF）或长期持续性（慢性）AF（cAF）患者的心房全组织裂解物和CM中的NLRP 3-炎性体活化。为了确定NLPR 3的CM特异性活化是否足以促进AF，建立了表达组成型活性NLRP 3（CM-KI）的CM特异性敲入小鼠模型。体内电生理学用于评估房性心律失常的脆弱性。为了评价AF的机制，在CM-KI小鼠和WT同窝小鼠中评价了电激动模式、Ca 2+火花频率（CaSF）、心房有效不应期（AERP）和心房形态。在pAF和cAF患者的心房CM中，NLRP 3-炎性体活性增加。CM-KI小鼠出现自发性房性期前收缩和诱导性AF，其被特异性NLRP 3-炎性体抑制剂MCC 950减弱。CM-KI小鼠出现异位活动、肌浆网钙释放异常、AERP缩短和心房肥大。腺相关病毒亚型9介导的CM特异性敲低Nlrp 3抑制了CM-KI小鼠AF的发生。最后，NLRP 3的遗传抑制防止AF的发展CREM转基因小鼠，一个良好的特征小鼠模型的自发性AF。我们的研究建立了一个新的病理生理作用CM NLRP 3-炎性体信号与AF的发病机制的联系，并建立了抑制NLRP 3作为一个潜在的新的AF治疗方法。
Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The “NACHT, LRR and PYD domain containing protein 3” (NLRP3)-inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells, but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome in AF. NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF (cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electrical activation pattern, Ca2+ spark frequency (CaSF), atrial effective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and WT littermates. NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic-reticulum Ca2+-release, AERP shortening and atrial hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes inhibition of NLRP3 as a potential novel AF-therapy approach.