Abstract 16413: A New Therapeutic Modality for Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia/Reperfusion Injury in Rats
Background: Pretreatment with statins at high doses is known to reduce ischemia-reperfusion (IR) injury by activating reperfusion injury salvage kinase, whereas its efficacy is not satisfactory in clinical settings. Nanoparticle (NP)-mediated drug delivery system may be promising for targeting reperfused myocardium with enhanced vascular permeability. Hence we tested the hypothesis that NP-mediated delivery of pitavastatin into ischemic myocardium ameliorates IR injury.
Methods and Results: In the rat model of 30-min myocardial ischemia followed by reperfusion, we intravenously (IV) injected 0.1 mg FITC solution or PLGA-NP containing 0.1 mg FITC at the time of reperfusion. Three hours after reperfusion, strong FITC signals were noted exclusively in cardiomyocytes within IR myocardium in NP groups (Figure A), whereas not in FITC solution group. IV injection of pitavastatin-NP containing 1.0 mg/kg pitavastatin, but not pitavastatin solution (1.0, 10 mg/kg), significantly reduced infarct size 24 hours after reperfusion (Figure B). Tissue concentration of pitavastatin in IR myocardium was significantly greater in pitavastatin-NP group than in pitavastatin solution group at 3 hours after reperfusion (P< 0.05). Pretreatment of wortmannin abolished the therapeutic effects of pitavastatin-NP (Figure B). Pitavastatin-NP increased p-Akt (Ser 473) and p-GSK3β(S9A) in IR myocardium (Figure C). Histological analysis showed that pitavastatin-NP reduced TUNEL-positive cells in infarct-border area (P<0.05), leukocytes infiltration in area at risk (P<0.001), and MCP-1 expression in area at risk (P<0.05) than vehicle group.
Conclusions: NP-mediated delivery of pitavastatin into ischemic myocardium at the time of reperfusion reduced myocardial infarct size by activating PI3K-Akt pathway and inhibiting leukocyte infiltration in rat IR model. This NP-based technology can be a new therapeutic modality for cardioprotection from IR injury.
- © 2012 by American Heart Association, Inc.