rhMG53 induces pharmacological preconditioning by acting as an agonistic ligand of c-Met

Ischemic heart disease (IHD) is a major cause of global mortality and disability. Reperfusion, the primary treatment for IHD, can exacerbate myocardial damage through ischemia-reperfusion (I/R) injury. Mitsugumin 53 (MG53/TRIM72), a muscle-specific E3 ligase, serves as an integral component of the cell membrane repair machinery and plays an essential role in cardioprotection. This study explores the cardioprotective mechanism of recombinant human MG53 (rhMG53) against I/R injury. We observed that rhMG53 is internalized via endocytosis and functions as an agonistic ligand for Mesenchymal-epithelial transition factor (c-Met). rhMG53/c-Met activates both the reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pro-survival pathways in cardiac myocytes. In vitro oxidative injury models and in vivo I/R injury experiments in MG53-deficient mice revealed that inactivating or knocking down c-Met abolished cardioprotective effects of rhMG53. These findings suggest that rhMG53-mediated cardioprotection relies on the activation of pro-survival pathways through the rhMG53/c-Met axis. rhMG53, as an agonistic c-Met ligand, triggers the activation of both RISK and SAFE pro-survival pathways, collectively contributing to its potent protection against myocardial I/R injury. These findings uncover a novel facet of MG53's functionality and provide insights into its mechanism of action in treating IHD. Furthermore, rhMG53/c-Met axis may be a promising avenue for developing novel treatments for IHD and related cardiovascular conditions.