Rapamycin attenuates age-related atrial remodeling and fibrillation by targeting HIF-1α-mediated metabolic dysregulation

Background: Atrial fibrillation (AF) is an age-related disease associated with substantial morbidity and mortality. Although rapamycin stands as a foremost anti-aging therapy with proven efficacy in lifespan extension, a critical gap exists in understanding its impact on aging-induced atrial remodeling and AF susceptibility. Objective: This study aims to evaluate the therapeutic potential of rapamycin against aging-related AF and elucidate its underlying mechanisms. Methods: An aging-induced AF-susceptible mouse model was induced by D-galactose injection, followed by rapamycin diet. Subsequent evaluations included AF susceptibility, atrial electrical/structural remodeling, and mechanistic analyses. Results: Rapamycin significantly reduced aging-induced AF susceptibility. It also ameliorated atrial electrical and structural remodeling. Metabolically, it improved systemic insulin resistance, restored mitochondrial function and morphology, and counteracted aging-induced perturbations in substrate utilization. Mechanistically, rapamycin inhibited hypoxia inducible factor-1α (HIF-1α) transcriptional activity, a key metabolic target in the aging process. Cellular experiments confirmed that rapamycin directly suppressed CoCl₂-induced HIF-1α expression and nuclear translocation, and pharmacological restoration of HIF-1α effectively attenuates the protective effects of rapamycin against D-galactose-induced atrial structural remodeling. Furthermore, molecular docking, dynamics simulations and isothermal titration calorimetry (ITC) suggested that rapamycin may also directly interfere with HIF-1α dimerization. Importantly, restoration of mTOR activity failed to reverse rapamycin-mediated HIF-1α inhibition, suggesting an mTOR-independent regulatory mechanism. Conclusion: Our findings demonstrate that rapamycin mitigates aging-induced atrial remodeling and AF susceptibility in mice, primarily through the inhibition of HIF-1α and the amelioration of downstream metabolic dysregulation.