Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation

Autor: Issam Abu-Taha, Scott A. LeMaire, Luge Li, Katherina M. Alsina, Larry D. Scott, Prince Jeyabal, Dobromir Dobrev, Shuyi Cao, Corey L. Reynolds, Ying H. Shen, Shokoufeh Ghezelbash, Ali El-Armouche, Xander H.T. Wehrens, Gong Chen, Xiaolu Pan, Tina Veleva, Christine Beeton, Stanley Nattel, Chunxia Yao, Wilhelm Schmitz, N. Tony Eissa, Frank U. Müller, Na Li
Rok vydání: 2018
Předmět:
0301 basic medicine
Genetically modified mouse
Patch-Clamp Techniques
Premature atrial contraction
Inflammasomes
Medizin
030204 cardiovascular system & hematology
Pharmacology
Heterocyclic Compounds
4 or More Rings
Pathogenesis
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
Dogs
Physiology (medical)
Atrial Fibrillation
NLR Family
Pyrin Domain-Containing 3 Protein
medicine
Animals
Humans
Myocytes
Cardiac
Sulfones
RNA
Small Interfering
Furans
Mice
Knockout
Gene knockdown
Sulfonamides
business.industry
Atrial fibrillation
Inflammasome
Electroencephalography
Arteries
Hypertrophy
medicine.disease
Pathophysiology
Disease Models
Animal
Sarcoplasmic Reticulum
030104 developmental biology
Indenes
Calcium
RNA Interference
Cardiology and Cardiovascular Medicine
business
medicine.drug
Signal Transduction
Zdroj: Circulation. 138(20)
ISSN: 1524-4539
Popis: Background: Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The NLRP3 (NACHT, LRR, and PYD domain containing protein 3) 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. Methods: NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal AF or long-standing persistent (chronic) AF. To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knockin 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, electric activation pattern, Ca 2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. Results: NLRP3 inflammasome activity was increased in the atrial CMs of patients with paroxysmal AF and chronic AF. 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 Ca 2+ release, atrial effective refractory period 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. Conclusions: Our study establishes a novel pathophysiological role for CM NLRP3 inflammasome signaling, with a mechanistic link to the pathogenesis of AF, and establishes the inhibition of NLRP3 as a potential novel AF therapy approach.
Databáze: OpenAIRE
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