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 h2o2-induced oxidative stress that mimicked ir injury. pretreatment with mdivi1-np ameliorated h2o2-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. © 2016 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.