Abstract 258: Nanoparticle-mediated Targeting of a Chemical Inhibitor of Drp1 to the Mitochondria Induces Cardioprotection From Myocardial Ischemia-reperfusion Injury

Abstract

Background: Mitochondria (MITO) injury including MITO permeability transition pore (mPTP) opening plays a major role in the mechanism of ischemia-reperfusion (IR) injury. Intravenous administration of an inhibitor of mPTP opening, cyclosporine A, can reduce IR injury in animals and patients with acute myocardial infarction (MI), however; the power of cardioprotection by cyclosporine A is insufficient. We tested the hypothesis that nanoparticle-mediated targeting of Mdivi1, a chemical inhibitor of Drp1, to MITO enhances cardioprotection from IR injury. Methods and Results: We formulated poly(lactic acid/glycolic acid) (PLGA) nanoparticles containing Mdivi1 (Mdivi1-NP) or FITC (FITC-NP). In neonatal rat cardiomyocytes, PLGA nanoparticles accumulated in MITO after the addition of hydrogen peroxide (H2O2) that represents oxidative stress during IR (Fig.A). Treatment with Mdivi1-NP reduced H2O2-induced MITO division and cardiomyocyte death (Fig.B). This Mdivi1-NP cardioprotective effect was not seen over adenovirus harboring Drp1 shRNA transduced cardiomyocyte. In an in vivo and ex vivo murine model, treatment with Mdivi1-NP at the time of reperfusion reduced infarct size more effectively than Mdivi1 alone (Fig.C). Interestingly, Mdivi1-NP inhibited the leakage of cytochrome c to cytosol and MITO swelling, and reduced IR injury in both wildtype and cyclophilin D (a key regulatory molecule for mPTP opening)-KO mice (Fig.D). Conclusions: Mdivi1-NP enhanced cardioprotection against IR injury through mechanisms independent of mPTP opening. Mdivi1-NP can be a novel cardioprotective strategy in acute MI.