Single local delivery of 5′-(N-ethylcarboxamido)adenosine depots ameliorates myocardial infarction-induced cardiac dysfunction via the enhancement of mitostasis

Myocardial infarction (MI) stands as a prominent contributor to global mortality. Despite existing therapies, there are notable shortcomings in delivering optimal cardiac support and reversing pathological progression, particularly within early stages. Adenosine presents a promising therapeutic target; however, its clinical utility is impeded by inherent limitations. In this study, an advanced strategy using adenosine agonist is pioneered to ameliorate MI-induced myocardial damage. Herein, an adenosine derivative 5′-(N-ethylcarboxamido) adenosine (NECA) is employed, and its therapeutic efficacy is evaluated via single local delivery into infarcted myocardium following MI. NECA displays remarkable benefits in endothelial cells and cardiomyocytes under both normoxic and hypoxic conditions. Likewise, single localized NECA delivery via newly developed NECA-loaded micro-depots demonstrates advanced improvement in cardiac function and prevention of myocardial damage in a MI mouse model, with notable promotion of angiogenesis and suppression in inflammation, oxidation, and apoptosis. Mechanistically, NECA exerts myocardial benefits via the enhancement of mitostasis by triggering AMP-activated protein kinase α (AMPKα) phosphorylation and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α) activation. These findings highlight the clinical significance of adenosine agonist NECA in cardiac support and recovery, with the single-delivered depots providing an advanced intervention for individuals with critically severe MI in the early phase.