Age-associated cardiac remodeling, characterized by hypertrophy and fibrosis, is a major contributor to cardiovascular morbidity in the elderly and is often exacerbated by metabolic stressors such as hypercholesterolemia. Given the central role of mitochondrial dysfunction in these processes, we investigated whether mitochondria-targeted esculetin (Mito-Esc) could mitigate pathological cardiac remodeling associated with aging and hypercholesterolemia. To model this condition, we utilized 12-month-old Apoe-/- mice, which exhibit chronic hypercholesterolemia and develop age-related cardio-metabolic structural alterations. The efficacy of Mito-Esc was compared with metformin, a putative geroprotective agent. Treatment with Mito-Esc or metformin significantly attenuated cardiac hypertrophy, fibrosis, inflammation, and oxidative stress in aged Apoe-/- mice. These protective effects were further validated in vitro using H9c2 cardiomyocytes and primary adult mouse cardiac fibroblasts. Mechanistically, both Mito-Esc and metformin exerted cardioprotective effects through activation of the AMPK-SIRT1 signaling axis. Depletion of either AMPK or SIRT1 markedly reduced the ability of these compounds to suppress cellular senescence, hypertrophic responses, and fibrotic signaling, indicating a critical role for this pathway. AMPK functioned upstream of SIRT1, as SIRT1 activation was attenuated following AMPK depletion. In parallel, both compounds significantly suppressed p38 MAPK activation. While depletion of AMPK or SIRT1 did not affect p38 MAPK activity, pharmacological inhibition of p38 MAPK enhanced AMPK and SIRT1 activation, supporting a model in which p38 MAPK activation negatively regulates the AMPK-SIRT1 axis. Collectively, these findings demonstrate that Mito-Esc alleviates pathological cardiac remodeling in the setting of aging and hypercholesterolemia through coordinated activation of AMPK-SIRT1 signaling and inhibition of p38 MAPK.
