Journal Article

Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening

Sunagawa, Kenji, Egashira, Kensuke, Ikeda, Gentaro, Nakano, Kaku, Nagaoka, Kazuhiro, Funamoto, Daiki, Nakano, Yasuhiro, Ishikita, Ayako, Matoba, Tetsuya

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 13/51 / 14/19 / 14/28 / 59/5 / 631/154/152 / 631/61/350/354 / 64 / 64/60 / 692/699/75/2/1674 / 82/51 / 96/31 / Animals / bcl-2-Associated X Protein - metabolism / Cardiomyocytes / Cardiotonic Agents - chemistry / Cardiotonic Agents - pharmacology / Cardiotonic Agents - therapeutic use / Cells, Cultured / Cyclosporine - chemistry / Cyclosporine - pharmacology / Cyclosporine - therapeutic use / Cyclosporins / Cytochromes c - metabolism / Disease Models, Animal / Drug Carriers - chemistry / Glycolic acid / Heart / Humanities and Social Sciences / Hydrogen peroxide / Hydrogen Peroxide - toxicity / Inflammation / Ischemia / Lactic Acid - chemistry / Male / Membrane permeability / Mice / Mice, Inbred C57BL / Mitochondria, Heart - drug effects / Mitochondria, Heart - metabolism / Mitochondrial DNA / Mitochondrial Membrane Transport Proteins - drug effects / Mitochondrial Membrane Transport Proteins - metabolism / Mitochondrial permeability transition pore / Monocytes / multidisciplinary / Myocardial infarction / Myocardial ischemia / Myocardial Reperfusion Injury - drug therapy / Myocardial Reperfusion Injury - metabolism / Myocardial Reperfusion Injury - pathology / Myocardium / Myocytes, Cardiac - cytology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Nanoparticles / Nanoparticles - chemistry / Oxidative stress / Oxidative Stress - drug effects / Permeability / Polyglycolic Acid - chemistry / Polylactide-co-glycolide / Rats / Rats, Sprague-Dawley / Reperfusion / Rodents / Science / Ventricle / Ventricular Remodeling - drug effects