A new therapeutic modality for acute myocardial infarction: Nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model

Kazuhiro Nagaoka, Tetsuya Matoba, Yajing Mao, Yasuhiro Nakano, Gentaro Ikeda, Shizuka Egusa, Masaki Tokutome, Ryoji Nagahama, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira

Research output: Contribution to journalArticle

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Abstract

Aim: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticlemediated targeting of pitavastatin protects the heart from IR injury. Methods and Results: In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11bpositive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. Conclusions: Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

Original languageEnglish
Article numbere0132451
JournalPloS one
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 13 2015

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myocardial infarction
phosphatidylinositol 3-kinase
nanoparticles
ischemia
Reperfusion Injury
Phosphatidylinositol 3-Kinases
Nanoparticles
Reperfusion
Rats
inflammation
animal models
Chemical activation
Myocardial Infarction
Inflammation
therapeutics
myocardium
Ischemia
glycolic acid
Myocardium
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

A new therapeutic modality for acute myocardial infarction : Nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model. / Nagaoka, Kazuhiro; Matoba, Tetsuya; Mao, Yajing; Nakano, Yasuhiro; Ikeda, Gentaro; Egusa, Shizuka; Tokutome, Masaki; Nagahama, Ryoji; Nakano, Kaku; Sunagawa, Kenji; Egashira, Kensuke.

In: PloS one, Vol. 10, No. 7, e0132451, 13.07.2015.

Research output: Contribution to journalArticle

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abstract = "Aim: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticlemediated targeting of pitavastatin protects the heart from IR injury. Methods and Results: In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11bpositive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. Conclusions: Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.",
author = "Kazuhiro Nagaoka and Tetsuya Matoba and Yajing Mao and Yasuhiro Nakano and Gentaro Ikeda and Shizuka Egusa and Masaki Tokutome and Ryoji Nagahama and Kaku Nakano and Kenji Sunagawa and Kensuke Egashira",
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T1 - A new therapeutic modality for acute myocardial infarction

T2 - Nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model

AU - Nagaoka, Kazuhiro

AU - Matoba, Tetsuya

AU - Mao, Yajing

AU - Nakano, Yasuhiro

AU - Ikeda, Gentaro

AU - Egusa, Shizuka

AU - Tokutome, Masaki

AU - Nagahama, Ryoji

AU - Nakano, Kaku

AU - Sunagawa, Kenji

AU - Egashira, Kensuke

PY - 2015/7/13

Y1 - 2015/7/13

N2 - Aim: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticlemediated targeting of pitavastatin protects the heart from IR injury. Methods and Results: In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11bpositive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. Conclusions: Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

AB - Aim: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticlemediated targeting of pitavastatin protects the heart from IR injury. Methods and Results: In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11bpositive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. Conclusions: Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

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