Abstract 17380: Nanoparticles-Mediated Delivery of Pioglitazone Reduces Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-mediated Inflammation in Mice and Mini Pigs
Background: Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury that hampers reperfusion therapy for acute myocardial infarction (MI); however, no anti-inflammatory therapy has been developed in clinical settings. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocytes. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into IR heart ameliorates IR injury in preclinical animal models.
Methods and Results: We formulated poly(lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NP) and a fluorescence marker FITC (FITC-NP). In a mouse model of myocardial IR injury, intravenous administration of FITC-NP at the time of reperfusion yielded significantly higher FITC signals in the IR myocardium and in monocytes in the circulating blood IR heart. Intravenous treatment with Pio-NPs containing ≥0.1 mg/kg of pioglitazone at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662 (Fig. A). In contrast, pioglitazone solution at doses up to 3.0 mg/kg showed no therapeutic effects (Fig. A). Pio-NP, but not control nanoparticles, inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart (Fig. B). Fluorescence molecular tomography for cathepsin B supported anti-inflammatory effects of Pio-NP in the IR heart (Fig. C). Pio-NP showed no therapeutic effects in mice lacking CCR2 (a receptor for monocyte chemoattractant protein-1). In a conscious mini-pig model of myocardial IR injury, Pio-NP induced cardioprotection from IR injury, indicating the pre-clinical proof of concept.
Conclusion: Nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes in IR heart can be developed as a novel modality that offers organ protection by antagonizing monocyte-mediated inflammation in acute MI.
Author Disclosures: M. Tokutome: None. T. Matoba: None. Y. Nakano: None. K. Nakano: None. K. Sunagawa: None. K. Egashira: None.
- © 2014 by American Heart Association, Inc.