Regulation of acute myocardial infarction by CircTMCC1 through mitochondrial dysfunction and AMPK/mTOR-driven M1...

Circular RNAs (circRNAs) have been implicated in various cardiovascular diseases and hold promise as diagnostic biomarkers and therapeutic targets. However, the roles and mechanisms of circRNAs in coronary artery disease (CAD) and its severe complication, acute myocardial infarction (AMI), remain unclear. CircRNA sequencing, fluorescence in situ hybridization, and quantitative PCR were used to assess circTMCC1 expression in human coronary artery segments, peripheral blood mononuclear cells (PBMCs) from CAD patients, M1 macrophages, and an AMI mouse model. Multiple analytical methods were employed to investigate the predictive value of circTMCC1 for quantitative flow ratio (QFR) measurements. In vitro, we employed plasmid overexpression, small interfering RNA transfection, flow cytometry, immunofluorescence, reactive oxygen species (ROS), and mitochondrial membrane potential assays. In vivo, Masson's trichrome, hematoxylin and eosin staining, and immunohistochemistry were performed. Mechanistic investigations included bioinformatics, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, western blotting, and immunofluorescence. CircTMCC1 was significantly upregulated in CAD patients (p < 0.001) and associated with poor prognosis in AMI mouse models. CircTMCC1 was highly expressed in M1 macrophages (p < 0.001), and silencing its expression reduced M1 polarization, improved cardiac function after infarction, and regulated mitochondrial autophagy. Mechanistically, circTMCC1 facilitates the interaction between annexin A1 and the E3 ligase TRIM38, leading to annexin A1 degradation. Additionally, the AMPK/mTOR signaling pathway was identified as a downstream target of circTMCC1. These findings suggest that circTMCC1 may serve as a promising diagnostic biomarker and therapeutic target for CAD and AMI, potentially improving prognosis.