Abstract 260: Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion Injury
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Abstract
Background: Targeting one mediator of myocardial ischemia-reperfusion (IR) injury failed to reduce infarct size in clinical trials, suggesting the necessity of the innovative strategy to target more than 2 mediators simultaneously. Previously, we have engineered poly(lactic acid/glycolic acid) nanoparticle containing cyclosporine A (CsA-NP) and pitavastatin (Pitava-NP), and reported that the former inhibits the opening of mitochondrial permeability transition pore (mPTP) and the latter reduces monocyte-mediated inflammation in IR hearts. Here we tested the hypothesis that nanoparticle-mediated simultaneous targeting to mPTP and monocytes confers additive cardioprotection against IR injury.
Methods and Results: We produced mice deficient with both cyclophilin D (CypD, a key molecule for mPTP opening) and CCR2 (a receptor for monocyte chemoattractant protein-1), and found that the double-KO mice displayed dramatic reduction in myocardial IR injury model (Fig. A). Flow cytometric analysis and fluorescence molecular tomography showed that inflammation was markedly inhibited in CCR2-KO and CypD/CCR2-KO mice while residual inflammation was noted in CypD-KO mice. In CypD mice, Pitava-NP reduced recruitment of Ly6Chigh inflammatory monocytes and showed therapeutic effects (Fig. B). In contrast, CsA-NP reduced IR injury in CCR2-KO mice. Simultaneous treatment with CsA-NP and Pitava-NP at the time of reperfusion showed additive reduction in IR injury in wild-type mice (Fig. C).
Conclusions: Nanoparticle-mediated simultaneous targeting to mitochondria and inflammatory monocytes can be developed as a novel therapeutic strategy in IR injury.

Author Disclosures: G. Ikeda: None. T. Matoba: None. A. Ishikita: None. K. Egashira: None.
- © 2015 by American Heart Association, Inc.
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- Abstract 260: Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion InjuryGentaro Ikeda, Tetsuya Matoba, Ayako Ishikita and Kensuke EgashiraCirculation Research. 2015;117:A260, originally published October 21, 2015
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- Abstract 260: Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion InjuryGentaro Ikeda, Tetsuya Matoba, Ayako Ishikita and Kensuke EgashiraCirculation Research. 2015;117:A260, originally published October 21, 2015