Rationale: Ischemic heart disease is a leading cause of death in human population and protection of myocardial infarction (MI) associated with ischemia-reperfusion (I/R) injury remains a challenge. MG53 is an essential component of the cell membrane repair machinery that protects injury to the heart.
Objective: We investigated the therapeutic value for using the recombinant human MG53 (rhMG53) protein for treatment of MI.
Methods and Results: Using Langendorff perfusion of isolated mouse heart, we found that I/R caused injury to cardiomyocytes and release of endogenous MG53 into the extracellular solution. The exogenous rhMG53 protein applied to the perfusion solution could concentrate at injury sites on the cardiomyocytes to facilitate cardioprotection. With rodent models of I/R-induced MI, we established the in vivo dosing range for rhMG53 in cardioprotection. Using a porcine model of angioplasty-induced MI, the cardioprotective effect of rhMG53 was evaluated. Intravenous administration of rhMG53, either prior to or post ischemia, reduced the infarct size and troponin I release in the porcine model when examined at 24 hrs post reperfusion. Biochemical study showed that the systemically delivered rhMG53 localized to the acute infarct zone of the porcine heart. Echocardiogram and histological analyses revealed that the protective effects for rhMG53 observed following acute MI led to long-term improvement in cardiac structure and function in the porcine model when examined at 4 weeks post operation.
Conclusions: Cardioprotection of rhMG53 in porcine model supports the concept that rhMG53 protein could have therapeutic value for treatment of MI in human patients with ischemic heart disease.