A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome.
Jia SongJiao WuDexter J RobichauxTingting LiShuyue WangMaria J Arredondo SancristobalBingning DongDobromir DobrevJason KarchSandhya S ThomasNa LiPublished in: Cells (2024)
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) Ca 2+ -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 Ca 2+ -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 2+ -release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.
Keyphrases
- atrial fibrillation
- catheter ablation
- left atrial
- oxidative stress
- oral anticoagulants
- high fat diet induced
- left atrial appendage
- direct oral anticoagulants
- heart failure
- percutaneous coronary intervention
- weight loss
- healthcare
- electronic health record
- dna damage
- signaling pathway
- body mass index
- insulin resistance
- climate change
- dna methylation
- metabolic syndrome
- reactive oxygen species
- machine learning
- risk assessment
- endothelial cells
- diabetic rats
- amino acid
- circulating tumor
- genome wide
- binding protein
- nucleic acid
- skin cancer
- drug induced
- mitral valve
- high glucose
- drug delivery
- heat shock