title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Ishikita
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan matoba@cardiol.med.kyushu-u.ac.jp egashira@cardiol.med.kyushu-u.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Gentaro
authors.initials: G
authors.lastname: Ikeda
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Koga
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kaku
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Labolatory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan matoba@cardiol.med.kyushu-u.ac.jp egashira@cardiol.med.kyushu-u.ac.jp.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems; D034281:Dynamins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D000067268:Isolated Heart Preparation; D019344:Lactic Acid / Q000627:therapeutic use; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles / Q000627:therapeutic use*; D016877:Oxidants / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects*; D011100:Polyglycolic Acid / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D021381:Protein Transport / Q000187:drug effects; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C494827:Bax protein, mouse; D001672:Biocompatible Materials; D004337:Drug Carriers; D016877:Oxidants; D052999:Quinazolinones; D051028:bcl-2-Associated X Protein; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: drug delivery system; ischemia‐reperfusion injury; mitochondria; myocardial infarction; nanoparticle