Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening.
Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening.
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DOI：
10.1038/srep20467
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发表时间：
2016-02-10
影响因子：
4.6
通讯作者：
Egashira K
中科院分区：
文献类型：
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作者：
Ikeda G;Matoba T;Nakano Y;Nagaoka K;Ishikita A;Nakano K;Funamoto D;Sunagawa K;Egashira K
心肌缺血再灌注（IR）损伤限制了急性心肌梗死（MI）早期再灌注治疗的治疗效果，其中线粒体通透性转换孔（mPTP）开放发挥着关键作用。我们的目的是确定聚乳酸/乙醇酸 (PLGA) 纳米颗粒介导的线粒体靶向抑制 mPTP 打开的分子环孢菌素 A (CsA) 是否能增强 CsA 诱导的心脏保护作用。在体内小鼠 IR 模型中，静脉注射的 PLGA 纳米粒子位于 IR 心肌线粒体处。再灌注开始时使用与 CsA 结合的纳米颗粒 (CsA-NP) 进行治疗，通过抑制 mPTP 开放，增强了单独 CsA 对 IR 损伤的心脏保护作用（如较低 CsA 浓度下 MI 大小减小所示）。 IR 后 28 天，左心室重构得到改善，但治疗并不影响炎症单核细胞向 IR 心脏的募集。在体外培养的大鼠心肌细胞中，添加过氧化氢后观察到线粒体 PLGA 纳米颗粒靶向，这代表 IR 期间的氧化应激，并被 CsA 阻止。 CsA-NP 可开发为有效的 mPTP 打开抑制剂，并可保护器官免受 IR 损伤。
Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.