Kupatt Christian, Hinkel Rabea, Lamparter Mathias, von Brühl Marie-Luise, Pohl Tilman, Horstkotte Jan, Beck Heike, Müller Susanne, Delker Sebastian, Gildehaus Franz-Josef, Büning Hildegard, Hatzopoulos Antonis K, Boekstegers Peter
Internal Medicine I, Klinikum Grosshadern, Munich, Germany.
Circulation. 2005 Aug 30;112(9 Suppl):I117-22. doi: 10.1161/CIRCULATIONAHA.104.524801.
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.
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 10(6) eEPCs by either pressure-regulated retroinfusion or intravenous transfusion. One hour after reperfusion, 99Tc-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 (TTC 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%).
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.
成年内皮祖细胞（EPCs）可减小心肌梗死面积并改善缺血后心肌功能。我们最近发现，源自7.5日龄小鼠的克隆胚胎EPCs（eEPCs）在肿瘤转移小鼠模型中特异性归巢至缺氧区域，但不会影响正常器官，也不会形成癌。在此，我们在临床前猪模型中评估了eEPCs在缺血再灌注后限制器官功能障碍的潜力。
对猪进行缺血（左前降支动脉闭塞60分钟）和再灌注（7天）处理。在缺血结束时，通过压力调节逆向灌注或静脉输注给予含有或不含有5×10⁶个eEPCs的培养基。再灌注1小时后，与静脉应用相比，逆向灌注后99Tc标记的eEPCs在缺血心肌中的植入程度高6倍。在24小时和7天后测定局部心肌功能（150次/分钟时的心内膜下节段缩短[SES]，以非缺血回旋支区域的百分比表示）和梗死面积（TTC存活和亚甲蓝排除法）。与培养基处理的动物相比，逆向灌注eEPCs可减小梗死面积（35±4%对51±6%）并改善左前降支区域心尖的局部心肌储备（SES 31±4%对6±8%），而静脉应用的效果则不太明显（梗死面积44±4%；SES 12±3%）。逆向灌注等量的新生冠状动脉内皮细胞（大鼠）对梗死面积（49±5%）和局部心肌储备（16±7%）均无影响。在再灌注24小时时检测到eEPCs依赖性效应（梗死面积34±7%对58±6%），且对渥曼青霉素共同应用敏感（50±5%）。
我们的研究结果表明，eEPCs可减轻临床前猪模型中的缺血再灌注损伤。快速效应（最早在24小时）表明酶介导的心脏保护作用发挥了作用，这至少部分涉及磷脂酰肌醇3激酶/AKT途径。
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