Abstract 18536: Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion Injury
Introduction: Mitochondrial injury and inflammation play temporally and spatially different roles in myocardial ischemia-reperfusion (IR) injury, which demand novel strategy to target these 2 mediators specifically. Previously, we have engineered poly (lactic-co-glycolic acid) nanoparticle containing cyclosporine A (CsA-NP) or pitavastatin (Pit-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.
Hypothesis: Nanoparticle-mediated simultaneous targeting to mPTP and monocytes confer additive cardioprotection against IR injury.
Methods and Results: We produced mice lacking 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). Fluorescence reflectance image (FRI) revealed that CypD deficiency reduced Annexin-positive infarct area in the center of ischemic area, compared with WT mice at 10 min after reperfusion (Fig. B). Although infarct areas were equivalent between WT and CCR2 KO mice at 10 min after reperfusion, CCR2 deficiency inhibited the expansion of the infarct area during 24 hours. Flow cytometric analysis and fluorescence molecular tomography showed that inflammation was markedly inhibited in CCR2 KO and double KO mice, but not in CypD KO mice at 24 hours after reperfusion (Fig. C). In CypD KO mice, Pit-NP reduced recruitment of Ly6Chigh inflammatory monocytes and infarct size, whereas CsA-NP reduced infarct size in CCR2 KO mice. Simultaneous treatment with CsA-NP and Pit-NP at the time of reperfusion reduced infarct size by an additive manner (Fig. D).
Conclusions: Nanoparticle-mediated simultaneous targeting to mitochondria and inflammatory monocytes can be developed as a novel therapeutic strategy for myocardial IR injury.
Author Disclosures: G. Ikeda: None. T. Matoba: None. K. Egashira: None.
- © 2015 by American Heart Association, Inc.