A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-01, Vol.13 (2), p.108
• Main Authors: Song, Jia, Wu, Jiao, Robichaux, Dexter J, Li, Tingting, Wang, Shuyue, Arredondo Sancristobal, Maria J, Dong, Bingning, Dobrev, Dobromir, Karch, Jason, Thomas, Sandhya S, Li, Na
• Format: Article
• Language: English
• Subjects: Absent-in-Melanoma; Animals; Antibodies; Arrhythmia; Atherosclerosis; Atrial fibrillation; Atrial Fibrillation - etiology; Atrial Fibrillation - metabolism; Calcium (reticular); Cardiac muscle; Cardiovascular disease; Care and treatment; Complications and side effects; Creatinine; Cytoplasm; Diet; Diet, High-Protein - adverse effects; DNA-Binding Proteins - metabolism; Glucose; Health aspects; Heart failure; High protein diet; inflammasome; Inflammasomes; Insulin; Kidney diseases; Laboratory animals; Melanoma; Metabolism; Mice; mitochondria; Mitochondrial DNA; Myocytes; Oxidative stress; Pathogenesis; Proteins; Sarcoplasmic reticulum; Weight control
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13020108

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 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 -HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca -release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca -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 Ca -release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.