represent the views of the Department of Veterans Affairs or the United States Government. ~~ ~~ Coronary heart disease is the leading cause of death worldwide, and acute myocardial infarction is the most severe type of the illness. Myocardial infarction size is a major determinant of clinical outcome/prognosis in patients with acute MI. Reduction in MI size has been partially achieved by early reperfusion therapy with thrombolytic drugs and/or percutaneous coronary intervention in those patients. However, the restoration of blood supply to the buy Varlitinib ischemic myocardium induces ischemia-reperfusion injury, which may limit the therapeutic effects of early reperfusion. Various pharmacological agents have been shown to reduce IR injury in animal models; however, none of them have been developed as cardioprotective modalities for IR injury in clinical practice. Therefore, there is an unmet need to develop innovative cardioprotective modalities to reduce IR injury. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are used worldwide as cholesterol-lowering drugs. In addition, statins are known to afford cardioprotection from IR injury in animals; pretreatment with statins at high doses before ischemia protects hearts from IR injury in vivo. These unique effects of statins on limiting MI size are not related to cholesterol-lowering, but are mediated by activating pro-survival protein kinase cascades such as the PI3 kinase /Akt pathway and by anti-inflammatory effects. The activation of such pro-survival signaling, referred to as the “reperfusion injury salvage kinase”, pathway attenuates reperfusion-induced necrosis and apoptosis, and thus reduces MI size, when administrated before IR. However, these MI-limiting effect was not replicated in animal models when administered at the time of reperfusion, which is clinically feasible time point of adjunctive therapeutic intervention upon reperfusion therapy for acute MI. In a recent placebo-controlled randomized clinical trial, pretreatment with atorvastatin 1030 min before primary PCI for ST-elevation acute MI patients failed to improve cardiac function, microvascular perfusion and to decreased MI size. This discrepancy in the efficacy of statins before ischemia and at reperfusion is attributed to insufficient local concentrations when administered at the time of reperfusion. To address this challenge, we developed a nanoparticle-mediated drug delivery system using bioabsorbable poly nanoparticle. We recently reported that nanoparticle-mediated delivery of pitavastatin showed significant therapeutic effects on ischemia-induced neovascularization, pulmonary arterial hypertension and restenosis PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19741728 in animal models. Because the nanoparticle accumulates into diseased tissues/organs including IR myocardium via increased vascular permeability, we hypothesized that nanoparticle-mediated targeting of statins to IR myocardium can be a novel therapeutic modality for IR injury. In the present study, we used a rat IR model and tested the hypothesis PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19741295 that nanoparticles are selectively delivered to IR myocardium after intravenous injection at the time of reperfusion and 
nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury as seen by reduction in MI size and improvement of left ventricular function. 2 / 23 Nanomedicine for Myocardial Reperfusion Injury Material and Methods Preparation of PLGA nanoparticle PLGA with an average molecular weight of 20,000 and a copolymer ratio of lac