Abstract 15381: Nanoparticle-mediated Delivery of Pioglitazone Ameliorates Inflammation and Inhibits Atherosclerotic Plaque Rupture in Apolipoprotein-E Deficient Mice
Background: Monocytes/macrophages play major roles in atherosclerotic plaque destabilization and rupture. Although PPARγ agonist including pioglitazone enhances alternative activation of monocytes/macrophages, its clinical use is hampered by adverse effects including heart failure. Therefore, we hypothesized that nanoparticle (NP)-mediated delivery of pioglitazone regulates monocytes/macrophages polarity and inhibits plaque rupture.
Methods and Results: We developed bioabsorbable poly-lactic-glycolic-acid (PLGA) NP for effective drug delivery to atherosclerotic plaques. FACS analysis 2 days after intravenous injection of FITC-NP revealed that the NPs were effectively delivered to both circulating monocytes and aortic macrophages. Single injection of pioglitazone-NP (pio-NP) reduced circulating Ly6Chigh monocytes. Weekly intravenous administration of pio-NP (containing 0.7 or 7 mg/kg pioglitazone) for 4 weeks reduced atherosclerotic plaque rupture in the brachiocephalic arteries of apolipoprotein E-deficient mice fed with high-fat diet and infused with angiotensin II, compared with control NP, whereas daily oral treatment (1 mg/kg per day) did not (Fig. A). Fluorescent reflectance imaging showed that pio-NP inhibits MMP activities in the atherosclerotic plaques (Fig. B). In classically-activated bone marrow-derived macrophages, pretreatment with pio-NP increased anti-inflammatory IL-4 expression and decreased expression of IL-1β and extracellular MMP inducer (EMMPRIN). Finally, oral treatment with pioglitazone induced expression of the epithelial Na channel-α (ENaC-α) in kidneys, which is implicated in fluid retention and heart failure, whereas pio-NP did not.
Conclusion: Monocyte-targeting delivery of pio-NP is a promising strategy to prevent atherosclerotic plaque rupture with a safety profile.
Author Disclosures: S. Nakashiro: None. T. Matoba: None. J. Koga: None. K. Nakano: None. K. Sunagawa: None. K. Egashira: None.
- © 2014 by American Heart Association, Inc.