ID2 attenuates post-MI ventricular arrhythmias by targeting GATA4 suppression to preserve mitochondrial function and Na+/K+-ATPase activity.

OBJECTIVES: Post-myocardial infarction (MI) ventricular arrhythmia (VA) remains a leading cause of sudden cardiac death. Current antiarrhythmic drugs often fail to target the core metabolic-structural remodeling underlying arrhythmias. The transcriptional repressor ID2, which has been implicated in cardiovascular development, remains poorly characterized regarding its role and contribution to VA pathogenesis. This study investigated the role of the transcriptional repressor ID2 in post-myocardial infarction ventricular arrhythmia. METHODS: An MI rat model was established via left anterior descending (LAD) coronary artery ligation. ID2 expression in myocardial tissues was quantified by immunofluorescence and western blot. Flow cytometry and biochemical assays were employed to evaluate the impact of ID2 modulation on arrhythmogenesis. Hypoxia-challenged cardiomyocytes treated with rotenone (Complex I inhibitor) and digoxin (Na+/K+-ATPase inhibitor) were used to investigate ID2's effects on mitochondrial dysfunction and Na+/K+-ATPase activity. Mechanistic studies of ID2 included STRING interaction detection, immunofluorescence, and Pearson correlation analysis. RESULTS: ID2 expression was significantly downregulated in MI rats and was inversely correlated with PVC frequency and VT/VF duration. Overexpression of ID2 reduced arrhythmia severity scores and attenuated PVC/VT/VF incidence in MI rats; me'anwhile, it ameliorated mitochondrial dysfunction, as reflected by restored membrane potential and ATP levels and reduced ROS, and improved Na+/K+-ATPase dysregulation in hypoxia-induced cardiomyocytes. Mechanistically, ID2 directly bound to GATA4 and reduced its expression. Overexpression of ID2 attenuated mitochondrial dysfunction and preserved Na+/K+-ATPase activity in hypoxic cardiomyocytes, whereas GATA4 overexpression weakened ID2's protective effect. CONCLUSIONS: This study demonstrates that ID2 alleviates VA by suppressing GATA4 expression, thereby mitigating mitochondrial dysfunction and Na+/K+-ATPase dysregulation. These findings elucidate the ID2-GATA4 regulatory axis in VA pathogenesis, which may provide a previously unrecognized therapeutic target for arrhythmia management.