Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide.
Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide.
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DOI：
10.1161/jaha.112.001644
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发表时间：
2012-06
影响因子：
5.4
通讯作者：
Brown DA
中科院分区：
文献类型：
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作者：
Kloner RA;Hale SL;Dai W;Gorman RC;Shuto T;Koomalsingh KJ;Gorman JH 3rd;Sloan RC;Frasier CR;Watson CA;Bostian PA;Kypson AP;Brown DA
再灌注损伤的表现包括心肌细胞死亡导致心肌梗死、收缩功能障碍和以无复流现象为特征的血管损伤。线粒体产生的活性氧被认为在再灌注损伤的每个方面都起着中心作用，尽管目前还没有针对线粒体的治疗方法来减少再灌注损伤。我们研究了线粒体靶向多肽Bendavia(隐形多肽)在一系列实验性心肌缺血/再灌注模型中的心脏保护作用。缺血后给予Bendavia可使在体绵羊模型和体外豚鼠模型的心肌梗死面积分别减少15%(P=0.02)和38%至42%(P<；0.05)。在活体兔模型中，用硫代黄素S染色评估冠状动脉无复流的程度，在任何给定的缺血危险区域，本达维亚组显著小于对照组(P=0.0085)。心肌对苯达韦的摄取为每分钟25%的≈，并且在再灌流过程中摄取保持一致。在所研究的任何模型中，Bendavia均不影响缺血后心脏血流动力学的恢复。暴露在低氧/复氧环境中的分离的心肌细胞显示，用苯达维亚处理后存活率提高。这种保护似乎是通过降低活性氧介导的复氧过程中的细胞死亡，与维持Bendavia处理的心肌细胞的线粒体膜电位有关。在几种不同的损伤模型中，缺血后给予Bendavia可保护再灌注损伤。这些数据表明，Bendavia是一种线粒体靶向治疗，通过维持线粒体能量和抑制细胞内活性氧水平来减少再灌注损伤。(J am心脏协会。2012年；1：e001644 DOI：10.1161/JAHA.112.001644。)
Manifestations of reperfusion injury include myocyte death leading to infarction, contractile dysfunction, and vascular injury characterized by the “no-reflow” phenomenon. Mitochondria-produced reactive oxygen species are believed to be centrally involved in each of these aspects of reperfusion injury, although currently no therapies reduce reperfusion injury by targeting mitochondria specifically. We investigated the cardioprotective effects of a mitochondria-targeted peptide, Bendavia (Stealth Peptides), across a spectrum of experimental cardiac ischemia/reperfusion models. Postischemic administration of Bendavia reduced infarct size in an in vivo sheep model by 15% (P=0.02) and in an ex vivo guinea pig model by 38% to 42% (P<0.05). In an in vivo rabbit model, the extent of coronary no-reflow was assessed with Thioflavin S staining and was significantly smaller in the Bendavia group for any given ischemic risk area than in the control group (P=0.0085). Myocardial uptake of Bendavia was ≈25% per minute, and uptake remained consistent throughout reperfusion. Postischemic recovery of cardiac hemodynamics was not influenced by Bendavia in any of the models studied. Isolated myocytes exposed to hypoxia/reoxygenation showed improved survival when treated with Bendavia. This protection appeared to be mediated by lowered reactive oxygen species–mediated cell death during reoxygenation, associated with sustainment of mitochondrial membrane potential in Bendavia-treated myocytes. Postischemic administration of Bendavia protected against reperfusion injury in several distinct models of injury. These data suggest that Bendavia is a mitochondria-targeted therapy that reduces reperfusion injury by maintaining mitochondrial energetics and suppressing cellular reactive oxygen species levels. (J Am Heart Assoc. 2012;1:e001644 doi: 10.1161/JAHA.112.001644.)