title: Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening.
abstract: Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Gentaro
authors: G
authors: Ikeda
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Tetsuya
authors: T
authors: Matoba
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Yasuhiro
authors: Y
authors: Nakano
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Kazuhiro
authors: K
authors: Nagaoka
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Ayako
authors: A
authors: Ishikita
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.|Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors: Kaku
authors: K
authors: Nakano
authors: Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors: Daiki
authors: D
authors: Funamoto
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.
authors: Kenji
authors: K
authors: Sunagawa
authors: Department of Cardiovascular Medicine, Fukuoka, Japan.|Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors: Kensuke
authors: K
authors: Egashira
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000633:toxicity; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004337:Drug Carriers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051028:bcl-2-Associated X Protein; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016572:Cyclosporine; D045304:Cytochromes c; D006861:Hydrogen Peroxide