A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model.
A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model.
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DOI：
10.1371/journal.pone.0162425
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Egashira K
中科院分区：
文献类型：
--
作者：
Ichimura K;Matoba T;Nakano K;Tokutome M;Honda K;Koga J;Egashira K
存在开发用于急性心肌梗死的创新心脏保护模式的未满足的需求，对于急性心肌梗死，缺血-再灌注（IR）损伤阻碍了介入再灌注治疗。我们最近报道了生物可吸收聚（乳酸/乙醇酸）（PLGA）纳米颗粒介导的匹伐他汀（匹伐他汀-NP）治疗通过激活PI 3 K-Akt途径并抑制炎症，在大鼠IR损伤模型中发挥心脏保护作用。为了获得临床前概念验证证据，在本研究中，我们在清醒和麻醉的猪模型中检测了匹伐他汀-NP对心肌IR损伤的作用。在84只巴马小型猪的左回旋支冠状动脉（LCx）处手术植入气动袖带封堵器和遥测发射器，以连续监测心电图以及监测动脉血压和心率。LCx闭塞60分钟，然后在清醒条件下再灌注24小时。在再灌注前5分钟静脉注射含有≥ 8 mg/体匹伐他汀的匹伐他汀-NP可显著降低梗死面积;相比之下，单独使用匹伐他汀（8 mg/体）无治疗作用。匹伐他汀-NP对体外培养的心肌细胞具有抗凋亡作用。IR损伤后4周进行的心脏磁共振成像显示，匹伐他汀-NP降低了左心室重塑的程度。重要的是，匹伐他汀-NP对血压、心率或血清生化没有显著影响。在麻醉猪中的探索性检查显示了药代动力学分析和匹伐他汀-NP对无复流现象的影响。在临床前清醒猪模型中，NP介导的匹伐他汀递送至IR损伤的心肌对IR损伤发挥心脏保护作用，而没有明显的不良副作用。因此，匹伐他汀-NP代表了急性心肌梗死IR损伤的一种新的治疗方式。
There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models. Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon. NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.
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影响因子：
2.5
作者：
Bune, Laurids T;Larsen, Jens R;Thaning, Pia;Bune, Nethe E T;Rasmussen, Peter;Rosenmeier, Jaya B
通讯作者：
Rosenmeier, Jaya B
影响因子：
4.6
作者：
Nakano Y;Matoba T;Tokutome M;Funamoto D;Katsuki S;Ikeda G;Nagaoka K;Ishikita A;Nakano K;Koga J;Sunagawa K;Egashira K
通讯作者：
Egashira K
影响因子：
4.6
作者：
Ikeda G;Matoba T;Nakano Y;Nagaoka K;Ishikita A;Nakano K;Funamoto D;Sunagawa K;Egashira K
通讯作者：
Egashira K
影响因子：
5.8
作者：
Saxena, V;Sadoqi, M;Shao, J
通讯作者：
Shao, J
影响因子：
10.8
作者：
BARDAJI, A;CINCA, J;SCHOENENBERGER, A
通讯作者：
SCHOENENBERGER, A