Publication Date
1-5-2024
Journal
Cells
DOI
10.3390/cells13020108
PMID
38247800
PMCID
PMC10814244
PubMedCentral® Posted Date
1-5-2024
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Animals, Mice, Atrial Fibrillation, Cytoplasm, Diet, High-Protein, DNA-Binding Proteins, Inflammasomes, atrial fibrillation, high-protein diet, Absent-in-Melanoma, inflammasome, mitochondria
Abstract
High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2−/− mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the Aim2−/−-HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca2+-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in Aim2−/− mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca2+-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca2+-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.
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Cardiology Commons, Digestive System Diseases Commons, Gastroenterology Commons, Medical Sciences Commons, Oncology Commons
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