Abstract 8984: A New Therapeutic Modality for Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Myocardial Ischemia/Reperfusion Injury in Rats

Abstract

Background: In ST-elevation acute myocardial infarction (STEMI), early reperfusion is the most effective therapeutic strategy. Reperfusion, however, induces ischemia-reperfusion (I/R) injury that can paradoxically cancel the beneficial impacts of reperfusion. Pretreatment with statins at high doses before the occurrence of ischemia is known to reduce I/R injury by activating reperfusion injury salvage kinase (RISK) pathway, whereas treatment with statins at the time of reperfusion is reported to elicit no therapeutic effects. Nanoparticle (NP)-mediated drug delivery system may be promising for targeting reperfused myocardium where vascular permeability is enhanced. Hence we tested the hypothesis that NP-mediated site-specific delivery of pitavastatin into ischemic myocardium ameliorates I/R injury through activation of RISK pathway. Methods and Results: In the rodent model of 30-min myocardial ischemia and subsequent reperfusion, we intravenously (IV) injected NP containing 0.1 mg FITC or 0.1 mg FITC solution at the time of reperfusion. Three hours after reperfusion, we found, in the NP group, significant FITC fluorescence in viable cardiomyocytes within the area at risk (Figure A, B), while did not find in the FITC solution group (Figure B). IV treatment of pitavastatin-NP containing 1.0 mg/kg pitavastatin, but not pitavastatin solution (1.0, 10 mg/kg), reduced infarct size 24-hours after reperfusion (Figure C). Pitavastatin-NP activated RISK pathway such as Akt signals (enhanced phosphorylation at Thr 308) in the reperfused myocardium. Pretreatment of wortmannin, a PI3K inhibitor, blunted the therapeutic effects of pitavastatin-NP (Figure C). Conclusions: NP-mediated delivery of pitavastatin into ischemic myocardium at the time of reperfusion reduced myocardial infarct size by activating RISK pathway in rodent I/R model. This study may provide an innovative medical approach that complement current reperfusion therapy for STEMI.