Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation

Circulation. 2018 Nov 13;138(20):2227-2242. doi: 10.1161/CIRCULATIONAHA.118.035202.

Abstract

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, Ca2+ 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 Ca2+ 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.

Keywords: AAV9; NLRP3 inflammasome; atrial fibrillation; electrical remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / metabolism
  • Arteries / pathology
  • Atrial Fibrillation / drug therapy
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology*
  • Calcium / metabolism
  • Disease Models, Animal
  • Dogs
  • Electroencephalography
  • Furans / pharmacology
  • Furans / therapeutic use
  • Humans
  • Hypertrophy / etiology
  • Hypertrophy / prevention & control
  • Inflammasomes / metabolism
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Patch-Clamp Techniques
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sarcoplasmic Reticulum / metabolism
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use

Substances

  • Furans
  • Inflammasomes
  • MCC-950
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA, Small Interfering
  • Sulfonamides
  • Calcium