Potent cardioprotection from ischemia-reperfusion injury by a two-domain fusion protein comprising annexin V and Kunitz protease inhibitor.
Potent cardioprotection from ischemia-reperfusion injury by a two-domain fusion protein comprising annexin V and Kunitz protease inhibitor.
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由膜联蛋白V和Kunitz蛋白酶抑制剂的两域融合蛋白通过缺血再灌注损伤的有效心脏保护。
DOI：
10.1111/jth.12314
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Wun TC
中科院分区：
文献类型：
--
作者：
Yeh CH;Chen TP;Wang YC;Fang SW;Wun TC
大量证据表明，凝血蛋白酶（TF/FVIIa/FXa/凝血酶）及其靶蛋白酶激活受体（PAR-1/PAR-2）在心肌缺血再灌注损伤中起重要作用。我们推测，局部抑制缺血细胞膜表面的TF/FVIIa可以有效地阻断凝血级联反应和随后的PAR-1/PAR-2细胞信号转导，从而保护心肌免受I-R损伤。我们最近开发了一种膜联蛋白V-Kunitz抑制剂融合蛋白（ANV-6L 15），它可以特异性地结合凋亡细胞膜表面的阴离子磷脂，并有效地抑制膜锚定的TF/FVIIa。在这项研究中，我们研究了ANV-6L 15在大鼠心脏I-R模型中与水蛭素相比的心脏保护作用。在麻醉的Sprague道利大鼠中保持左冠状动脉闭塞45分钟，然后再灌注4小时。在冠状动脉结扎之前1分钟或之后2分钟，大鼠通过推注和连续输注接受ANV-6L 15（2.5至250 μg/kg）、媒介物或水蛭素的静脉推注。ANV-6L 15剂量依赖性地使梗死面积减少了87%，并使心肌肌钙蛋白I、TNF-α和sICAM-1的血浆水平分别降低了97%、96%和66%，对凝血参数几乎没有影响。ANV-6L 15还改善血流动力学紊乱，减少中性粒细胞浸润和减少TUNEL-（+）凋亡心肌细胞。水蛭素即使在超临床剂量下也不太有效。ANV-6L 15具有非常强的心脏保护作用，是预防心肌I-R损伤的有希望的候选药物。
Considerable evidence suggests that coagulation proteases (TF/FVIIa/FXa/thrombin) and their target protease activated receptors (PAR-1/PAR-2) play important roles in myocardial ischemia-reperfusion (I-R) injury. We hypothesized that localized inhibition of TF/FVIIa on the membrane surfaces of ischemic cells could effectively block coagulation cascade and subsequent PAR-1/PAR-2 cell signaling, thereby protecting the myocardium from I-R injury. We recently developed an annexin V-Kunitz inhibitor fusion protein (ANV-6L15) that could specifically bind to anionic phospholipids on the membrane surfaces of apoptotic cells and efficiently inhibit the membrane-anchored TF/FVIIa. In this study, we investigated the cardioprotective effect of ANV-6L15 in a rat cardiac I-R model in comparison to that of hirudin. Left coronary artery occlusion was maintained for 45 minutes followed by 4 hours of reperfusion in anesthetized Sprague Dawley rats. One minute before or 2 minutes after coronary ligation, rats received an i.v. bolus injection of ANV-6L15 (2.5 to 250 μg/kg), vehicle, or hirudin by bolus injection and continuous infusion. ANV-6L15 dose-dependently reduced infarct size by up to 87 %, and decreased plasma levels of cardiac troponin I, TNF-α, and sICAM-1, by up to 97 %, 96 %, and 66 %, respectively, with little impact on the coagulation parameters. ANV-6L15 also ameliorated hemodynamic derangements, attenuated neutrophil infiltration and reduced TUNEL-(+) apoptotic cardiomyocytes. Hirudin was less efficacious even at supra-clinical dose. ANV-6L15 confers exceptionally potent cardioprotection and is a promising drug candidate for prevention of myocardial I-R injury.
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DOI：
10.1152/ajpheart.1998.274.1.h242
发表时间：
1998-01-01
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
37.8
作者：
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影响因子：
37.8
作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
Coughlin, SR
影响因子：
5.7
作者：
Long, Ming;Yang, Lei;Tang, Lilong
通讯作者：
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