Retroinfusion of embryonic endothelial progenitor cells attenuates ischemia-reperfusion injury in pigs -: Role of phosphatidylinositol 3-kinase/AKT kinase
Retroinfusion of embryonic endothelial progenitor cells attenuates ischemia-reperfusion injury in pigs -: Role of phosphatidylinositol 3-kinase/AKT kinase
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DOI：
10.1161/circulationaha.104.524801
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发表时间：
2005-08-30
期刊：
影响因子：
37.8
通讯作者：
Boekstegers, P
中科院分区：
文献类型：
--
作者：
Kupatt, C;Hinkel, R;Boekstegers, P
成人内皮祖细胞（EPCs）减少心肌梗死面积和改善缺血后心肌功能。我们最近发现，克隆胚胎EPCs（eEPCs），来自7.5日龄的小鼠，家特异性缺氧地区的肿瘤转移小鼠模型，但备用正常器官，不形成癌。在这里，我们评估了潜在的eEPCs限制器官功能障碍后，缺血和再灌注在临床前猪model.Methods和Results-Pigs进行缺血（60分钟左前降支[LAD]动脉闭塞）和再灌注（7天）。在缺血结束时，我们通过压力调节的反向输注或静脉内输注施加含有或不含5 X IO 6个eEPC的培养基。再灌注后1小时，Tc-99标记的eEPCs在缺血心肌中的植入程度是静脉注射后的6倍。在24小时和7天后测定局部心肌功能（150/min时内膜下节段缩短[SES]，以非缺血性回旋支区域的百分比表示）和梗死面积（JTC活力和亚甲蓝排除）。与介质处理的动物相比，eEPCs的逆向输注减少了梗死面积（35 +/- 4%对51 +/- 6%），并改善了心尖LAD区域的局部心肌储备（SES 31 +/- 4%对6 +/- 8%），而静脉内应用显示出不太明显的效果（梗死面积44 +/- 4%; SES 12 +/- 3%）。反向输注等量的新生儿冠状动脉内皮细胞（大鼠）不影响梗死面积（49 +/- 5%）和局部心肌储备（16 +/- 7%）。在再灌注24小时检测到eEPC依赖性效应（梗死面积34 +/- 7%对58 +/- 6%），并且对Wortmannin coapplication 50 +/- 5%）敏感。快速效应（早在24小时）表明酶介导的心脏保护作用，其中涉及，至少部分，磷脂酰肌醇3-激酶/AKT途径。
Background-Adult endothelial progenitor cells (EPCs) reduce myocardial infarct size and improve postischemic myocardial function. We have recently shown that clonal embryonic EPCs (eEPCs), derived from 7.5-day-old mice, home specifically to hypoxic areas in tumor metastasis mouse models but spare normal organs and do not form carcinomas. Here, we assessed the potential of eEPCs to limit organ dysfunction after ischemia and reperfusion in a preclinical pig model.Methods and Results-Pigs were subjected to ischemia (60-minute left anterior descending [LAD] artery occlusion) and reperfusion (7 days). At the end of ischemia, we applied medium with or without 5 X 106 eEPCs by either pressure-regulated retroinfusion or intravenous transfusion. One hour after reperfusion, Tc-99-labeled eEPCs engrafted to a 6-fold higher extent in the ischemic myocardium after retroinfusion than after intravenous application. Regional myocardial function (subendocardial segment shortening [SES] at 150/min, given in percent of nonischemic circumflex region) and infarct size JTC viability and Methylene-blue exclusion) were determined 24 hours and 7 days later. Compared with medium-treated animals, retroinfusion of eEPCs decreased infarct size (35 +/- 4% versus 51 +/- 6%) and improved regional myocardial reserve of the apical LAD region (SES 31 +/- 4% versus 6 +/- 8%), whereas intravenous application displayed a less pronounced effect (infarct size 44 +/- 4%; SES 12 +/- 3%). Retroinfusion of an equal amount of neonatal coronary endothelial cells (rat) did not affect infarct size (49 +/- 5%) nor regional myocardial reserve (16 +/- 7%). The eEPC-dependent effect was detected at 24 hours of reperfusion (infarct size 34 +/- 7% versus 58 +/- 6%) and was sensitive to Wortmannin coapplication (50 +/- 5%).Conclusion-Our findings show that eEPCs reduce ischemia-reperfusion injury in a preclinical pig model. The rapid effect (as early as 24 hours) indicates a role for enzyme-mediated cardioprotection, which involves, at least in part, the phosphatidylinositol 3-kinase/AKT pathway.