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

Ayako Ishikita, Tetsuya Matoba, Gentaro Ikeda, Jun Ichiro Koga, Kaku Nakano, Junichi Sadoshima, Kensuke Egashira

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
JournalJournal of the American Heart Association
Volume7
DOIs
Publication statusPublished - Jul 22 2016

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Myocardium
Mitochondria
Myocardial Infarction
Membranes
Wounds and Injuries
Cell Death
Cardiac Myocytes
Knockout Mice
Cytosol
Nanoparticles
Reperfusion
Therapeutics
Heart Injuries
Cytochromes c
Pharmaceutical Preparations
Cell Survival
Coronary Vessels
Oxidative Stress
Acids
mitochondrial permeability transition pore

Cite this

@article{ee1635be82604e80aef9d8ba692b8faa,
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 = "BackgroundMitochondria‐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 ResultsWe 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.ConclusionsMdivi1‐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.",
author = "Ayako Ishikita and Tetsuya Matoba and Gentaro Ikeda and Koga, {Jun Ichiro} and Kaku Nakano and Junichi Sadoshima and Kensuke Egashira",
year = "2016",
month = "7",
day = "22",
doi = "10.1161/JAHA.116.003872",
language = "English",
volume = "7",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - 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

T2 - A New Therapeutic Modality for Acute Myocardial Infarction

AU - Ishikita, Ayako

AU - Matoba, Tetsuya

AU - Ikeda, Gentaro

AU - Koga, Jun Ichiro

AU - Nakano, Kaku

AU - Sadoshima, Junichi

AU - Egashira, Kensuke

PY - 2016/7/22

Y1 - 2016/7/22

N2 - BackgroundMitochondria‐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 ResultsWe 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.ConclusionsMdivi1‐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.

AB - BackgroundMitochondria‐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 ResultsWe 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.ConclusionsMdivi1‐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.

U2 - 10.1161/JAHA.116.003872

DO - 10.1161/JAHA.116.003872

M3 - Article

VL - 7

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

ER -