A New Therapeutic Modality for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K/Akt Pathway and Anti-Inflammation in a Rat Model.

Kazuhiro Nagaoka,Yasuhiro Nakano,Masaki Tokutome,Yajing Mao,Ryoji Nagahama,Gentaro Ikeda,Kaku Nakano,Kensuke Egashira,Tetsuya Matoba,Shizuka Egusa,Kenji Sunagawa,John Calvert

doi:10.1371/journal.pone.0132451

Abstract

AimThere is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury.Methods and ResultsIn a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium.ConclusionsNanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

Highlights

Coronary heart disease is the leading cause of death worldwide, and acute myocardial infarction (MI) is the most severe type of the illness [1]
The therapeutic effects of Pitavastatin-NP were blunted by a PI3 kinase (PI3K) inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A
Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for acute myocardial infarction (AMI)

Summary

Introduction

Coronary heart disease is the leading cause of death worldwide, and acute myocardial infarction (MI) is the most severe type of the illness [1]. Myocardial infarction (MI) size is a major determinant of clinical outcome/prognosis in patients with acute MI [2]. Reduction in MI size has been partially achieved by early reperfusion therapy with thrombolytic drugs and/or percutaneous coronary intervention in those patients. Various pharmacological agents have been shown to reduce IR injury in animal models; none of them have been developed as cardioprotective modalities for IR injury in clinical practice [3,4,5]. There is an unmet need to develop innovative cardioprotective modalities to reduce IR injury

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Results

Conclusion