{"id":6238,"date":"2023-02-17T07:03:04","date_gmt":"2023-02-17T07:03:04","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2018-enhanced-cardiomyocyte-nlrp3-inflammasome-signaling-promotes-atrial-fibrillation\/"},"modified":"2023-02-17T07:03:04","modified_gmt":"2023-02-17T07:03:04","slug":"2018-enhanced-cardiomyocyte-nlrp3-inflammasome-signaling-promotes-atrial-fibrillation","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2018-enhanced-cardiomyocyte-nlrp3-inflammasome-signaling-promotes-atrial-fibrillation\/","title":{"rendered":"2018 &#8211; Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation"},"content":{"rendered":"<p>Background:Atrial fibrillation (AF) is frequently associated with enhanced inflammatory\u00a0response. The \u201cNACHT, LRR and PYD domain containing protein 3\u201d (NLRP3)-inflammasome\u00a0mediates caspase-1 activation and interleukin-1\u03b2 release in immune cells, but is not known to\u00a0play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome\u00a0in AF.Methods:NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue\u00a0lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF\u00a0(cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a\u00a0CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) wasestablished. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To\u00a0evaluate the mechanism of AF, electrical activation pattern, Ca<sup>2+<\/sup>\u00a0spark frequency (CaSF), atrialeffective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and\u00a0WT littermates.Results:NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients.\u00a0CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which wasattenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited\u00a0ectopic activity, abnormal sarcoplasmic-reticulum Ca<sup>2+<\/sup>-release, AERP shortening and atrialhypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of Nlrp3\u00a0suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AFdevelopment in CREM transgenic mice, a well-characterized mouse model of spontaneous AF.Conclusions:Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes\u00a0inhibition of NLRP3 as a potential novel AF-therapy approach.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[45],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[54],"target_categories":[61],"target_families":[333],"targets":[249],"resource_keyword":[],"class_list":["post-6238","resource_library","type-resource_library","status-publish","hentry","products_tags-port-a-patch","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv1-5"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6238","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6238"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6238"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6238"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6238"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6238"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6238"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6238"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6238"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6238"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}