NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias

Abstract

Aims Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the ‘NACHT, LRR & PYD Domains-containing Protein 3’ (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. Methods and Results Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased bodyweight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wildtype (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice. Conclusions These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

“…The Nod-like receptor (NLR) family of PRRs represented by NLRP3 inflammasome serves as innate immune sensors and participates in the recognition of “danger signals,” resulting in caspase-1 activation and release of interleukin-1β (IL-1β)/IL-18. A rise in body weight in patients, sheep, and mice has been shown to be accompanied with NLRP3-inflammasome activation in the heart and other organs ( 444 , 445 ). Antiobesity measures such as caloric restriction and exercise were shown to lower levels of adipose NLRP3, suppress inflammation, and improve insulin sensitivity in obesity.…”

“…This is supported by ablation of obesity-associated inflammasome activation in liver and fat depots along with improved insulin signaling with NLRP3 knockout ( 446 ). In the heart, NLRP3 ablation resisted pacing-induced AF in the face of high-fat intake, denoting a key role for NLRP3 inflammasome in obesity-induced atrial arrhythmogenesis ( 444 ). In another independent study, although deficiency of NLRP3 and the adaptor protein apoptosis-associated speck-like protein containing CARD domain (ASC or Pycard) retarded obesity-induced systemic inflammation, LV concentric remodeling and diastolic dysfunction without affecting cardiac hypertrophic response to high-fat diet-induced obesity.…”

Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

“…2021). In cases when anaesthesia was required, mice were anaesthetized by oxygen and 2% isoflurane as previously reported (Scott et al . 2021).…”

“…In addition, myocardium infarction (MI) injury in adult male mice (8 weeks) were induced by permanent ligation of the left anterior descending artery (LAD) as previously described (Wu et al 2021). In cases when anaesthesia was required, mice were anaesthetized by oxygen and 2% isoflurane as previously reported (Scott et al 2021). Animals were euthanized by dissecting the diaphragm under isoflurane anaesthesia, after which organs were harvested.…”

Cardiac cytokine therapy? Relevance of targeting inflammatory mediators to combat cardiac arrhythmogenic remodeling

“…In response to damage-, pathogen-, or lifestyle-associated stimuli, NLRP3 is activated, and NFκB signaling promotes the upregulation of IL-1β and IL-18, which induce the production of further inflammatory cytokines, including IL6, IL-17A, IFN-γ, or CCL2 [10] . Recent study from Larry Scott Jr. and collaborators have demonstrated that obesity-induced atrial arrhythmogenic remodeling is associated with increased NLRP3 activity [11] . In addition, diabetes-associated thromboinflammation was shown to be accompanied by increased activity of NLRP3 inflammasome and IL-1β expression [12] .…”