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

作者：Nagaoka, Kazuhiro; Matoba, Tetsuya; Mao, Yajing; Nakano, Yasuhiro; Ikeda, Gentaro; Egusa, Shizuka; Tokutome, Masaki; Nagahama, Ryoji; Nakano, Kaku; Sunagawa, Kenji; Egashira, Kensuke^*

来源：PLos One, 2015, 10(7): e0132451.

DOI：10.1371/journal.pone.0132451

• MITOCHONDRIAL PERMEABILITY TRANSITION
• GLYCOGEN-SYNTHASE KINASE-3-BETA
• INDUCED CARDIOMYOCYTE APOPTOSIS
• CELLULAR BIOLOGY
• OXIDATIVE STRESS
• EUROPEAN-SOCIETY
• WORKING GROUP
• MICE
• ISCHEMIA/REPERFUSION
• MONOCYTES

Aim
There 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 Results
In 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 GSK3 beta, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium.
Conclusions
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 AMI.

• 出版日期2015-7-13