Abstract 17538: Nanoparticle-Mediated Targeting of a Mitochondria Division Inhibitor, Mdivi-1, to the Mitochondria Induces Cardioprotection from Ischemia-Reperfusion Injury

Background: Mitochondria (MITO) injury plays a major role in the mechanism of myocardial ischemia-reperfusion (IR) injury. Intravenous administration of an inhibitor of MITO permeability transition pore (mPTP) opening, cyclosporine A, at the time of reperfusion can reduce IR injury in animals and patients with acute myocardial infarction (MI), however; the degrees of cardioprotection induced by cyclosporine A seem to be inadequate. Therefore, a more effective modality for inhibiting MITO injury must be developed for cardioprotection from IR injury in acute MI. Here we tested the hypothesis that nanoparticle-mediated targeting of mitochondrial division inhibitor-1 (mdivi-1) to MITO enhances cardioprotection from IR injury. Methods and Results: We formulated poly(lactic acid/glycolic acid) (PLGA) nanoparticles containing mdivi-1 (Mdivi1-NP) or FITC (FITC-NP). In neonatal rat cardiomyocytes, mitochondrial-targeting of nanoparticles was noted after the addition of hydrogen peroxide (H2O2) that represents oxidative stress during IR (Fig. A). Treatment with Mdivi1-NP (containing 5 μM mdivi-1) markedly attenuated H2O2-induced MITO-division and cardiomyocyte death (Fig. B). In Langendorff perfused mouse heart, treatment with Mdivi1-NP (5 and 50 μM) at the time of reperfusion enhanced the cardioprotection against IR injury achieved by mdivi1 alone (Fig. C). In an in vivo murine model of IR, treatment with Mdivi1-NP (1.2 mg/kg) at the time of reperfusion also enhanced the cardioprotection against IR injury achieved by mdivi1 alone. Interestingly, treatment with Mdivi1-NP reduced IR injury and MITO swelling in mice lacking cyclophilin D (a key regulatory molecule for mPTP opening) (Fig. D). Conclusions: Nanoparticle-mediated targeting of mdivi1 to the mitochondria enhanced cardioprotection against IR injury through mechanisms independent of mPTP opening. Mdivi1-NP can be developed as a new cardioprotective strategy in acute MI. ![][1] [1]: /embed/graphic-1.gif