Nanoparticle‐Mediated Delivery of Mitochondrial Division Inhibitor 1 to the Myocardium Protects the Heart From Ischemia‐Reperfusion Injury Through Inhibition of Mitochondria Outer Membrane Permeabilization: A New Therapeutic Modality for Acute Myocardial Infarction

BACKGROUND: Mitochondria‐mediated cell death plays a critical role in myocardial ischemia‐reperfusion (IR) injury. We hypothesized that nanoparticle‐mediated drug delivery of mitochondrial division inhibitor 1 (Mdivi1) protects hearts from IR injury through inhibition of mitochondria outer membrane permeabilization (MOMP), which causes mitochondrial‐mediated cell death. METHODS AND RESULTS: We formulated poly (lactic‐co‐glycolic acid) nanoparticles containing Mdivi1 (Mdivi1‐NP). We recently demonstrated that these nanoparticles could be successfully delivered to the cytosol and mitochondria of cardiomyocytes under H(2)O(2)‐induced oxidative stress that mimicked IR injury. Pretreatment with Mdivi1‐NP ameliorated H(2)O(2)‐induced cell death in rat neonatal cardiomyocytes more potently than Mdivi1 alone, as indicated by a lower estimated half‐maximal effective concentration and greater maximal effect on cell survival. Mdivi1‐NP treatment of Langendorff‐perfused mouse hearts through the coronary arteries at the time of reperfusion reduced infarct size after IR injury more effectively than Mdivi1 alone. Mdivi1‐NP treatment also inhibited Drp1‐mediated Bax translocation to the mitochondria and subsequent cytochrome c leakage into the cytosol, namely, MOMP, in mouse IR hearts. MOMP inhibition was also observed in cyclophilin D knockout (CypD‐KO) mice, which lack the mitochondrial permeability transition pore (MPTP) opening. Intravenous Mdivi1‐NP treatment in vivo at the time of reperfusion reduced IR injury in wild‐type and CypD‐KO mice, but not Bax‐KO mice. CONCLUSIONS: Mdivi1‐NP treatment reduced IR injury through inhibition of MOMP, even in the absence of a CypD/MPTP opening. Thus, nanoparticle‐mediated drug delivery of Mdivi1 may be a novel treatment strategy for IR injury.