Abstract P268: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Myocardial Ischemia/Reperfusion Injury

Background: In acute myocardial infarction, early myocardial reperfusion is the most effective therapeutic strategy. The reperfusion, however, induces ischemia-reperfusion (I/R) injury that paradoxically cancels the beneficial effects of reperfusion. Statins are known to activate reperfusion injury salvage kinase (RISK) pathway, but its efficacy is not enough to be used as cardioprotective therapy. Local delivery of statins might optimize cardioprotective effects of statins. Hence we tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into ischemic myocardium at the time of reperfusion ameliorates myocardial I/R injury. Methods and Results: In a rat model of 30-min ischemia followed by reperfusion, significant FITC signals were detected in cardiomyocytes within infarct areas after intravenous (IV) injection of FITC-NP at the time of reperfusion ( Figure A). No significant FITC signals were noted after IV injection of FITC only. IV injection of pitavastatin-NP that contained 1.0 mg/kg pitavastatin at reperfusion reduced infarct size ( Figure B). The therapeutic effects of pitavastatin-NP were associated with activation of RISK pathway such as Akt signals in the reperfused myocardium. Wortmannin blunted the therapeutic effects of pitavastatin-NP (Figure B). On the other hand, no therapeutic effects were noted after IV injection of pitavastatin alone (1.0, 10 mg/kg). Conclusions: In I/R injury, NPs were delivered selectively into reperfused myocardium possibly via enhanced permeability and retension effects. NP-mediated delivery of pitavastatin at the time of reperfusion reduced myocardial infarct size by activating RISK pathway.