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首页> 外文期刊>European journal of cardio-thoracic surgery: Official journal of the European Association for Cardio-thoracic Surgery >Non-viral in vivo thrombomodulin gene transfer prevents early loss of thromboresistance of grafted veins.
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Non-viral in vivo thrombomodulin gene transfer prevents early loss of thromboresistance of grafted veins.

机译：非病毒体内血栓调节蛋白基因转移可防止早期丧失移植静脉的血栓抗性。

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OBJECTIVE: Immediate loss of thrombomodulin activity in the endothelium of vein grafts has been demonstrated during 90 min exposure to arterial circulation; this loss of activity is ascribed as an important cause of early thrombosis. Conventional ex vivo gene transfection after vein harvest cannot cover this acute period immediately after implantation. We have established a highly efficient non-viral gene therapy protocol utilizing modified transferrin receptor-facilitated gene transfer. Using this technique, we examined whether in vivo thrombomodulin gene therapy, directed to the endothelium of rat veins 2 days prior to grafting, may prevent thromboresistance impairment of vein grafts under simulated arterial circulation. METHODS: Abdomen of SD rat was opened and cationic liposome:transferrin:thrombomodulin gene complexes or the vector without DNAs were applied to the inferior vena cava of rats while blood flow was reduced by proximal and distal clamping. After 2 days, the transfected veins were harvested and thrombomodulin expression and thromboresistance properties determined before and after exposure to an artificial circuit. RESULTS: The trial of gene transfection using variable doses of DNAs confirmed that 7.5 microg of total DNAs was the most efficient quantity for thrombomodulin gene transfection to IVCs, although accompanying an increase of gene expression in other downstream organs. By transfection of the thrombomodulin gene in IVCs, the generation capacity of activated protein C in venous endothelium increased three-fold compared with veins treated with vector alone (P<0.01). Under simulated arterial circulation, perfusion of veins treated with vector alone decreased thrombomodulin activity to 36% of preperfused levels (P<0.01), whereas transfected grafts preserved the activity at normal vein endothelium levels even after perfusion. Consequently, the increase in endothelial thrombin activity induced by simulated arterial circulation was markedly attenuated in transfected veins (P<0.01), while immunohistochemistry confirmed the preservation of endothelial lining. CONCLUSIONS: Transferrin receptor-facilitated in vivo gene transfer to the inferior vena cava resulted in sufficient thrombomodulin gene expression immediately after graft implantation and subsequent maintenance of thromboresistance even after exposure to arterial pressure. Although further studies are needed, the present results suggest the possibility of gene therapy targeting acute phases of vein graft disease.
机译：目的：已证明在暴露于动脉循环的90分钟期间，静脉移植物的内皮中血栓调节蛋白活性立即丧失。这种活动丧失被认为是早期血栓形成的重要原因。静脉收获后常规的离体基因转染不能覆盖植入后的这一急性期。我们已经建立了利用修饰的转铁蛋白受体促进基因转移的高效非病毒基因治疗方案。使用这项技术，我们检查了在移植前2天针对大鼠静脉内皮的体内血栓调节蛋白基因治疗是否可以预防模拟动脉循环下静脉移植物的血栓抵抗性损害。方法：打开SD大鼠腹部，将阳离子脂质体：转铁蛋白：血栓调节蛋白基因复合物或不含DNA的载体应用于大鼠下腔静脉，同时通过近端和远端钳夹减少血流。 2天后，收集转染的静脉，并在暴露于人造电路之前和之后测定血栓调节蛋白的表达和血栓抵抗特性。结果：使用可变剂量DNA进行基因转染的试验证实，尽管伴随其他下游器官中基因表达的增加，但血栓调节素基因转染IVC的总量为7.5微克DNA最有效。通过IVCs中血栓调节蛋白基因的转染，与单独用载体处理的静脉相比，静脉内皮中活化蛋白C的生成能力增加了三倍（P <0.01）。在模拟的动脉循环下，仅用载体处理的静脉灌注将血栓调节蛋白活性降低至灌注前水平的36％（P <0.01），而转染的移植物即使在灌注后仍保持正常静脉内皮水平的活性。因此，在转染的静脉中，由模拟动脉循环引起的内皮凝血酶活性的增加明显减弱了（P <0.01），而免疫组织化学证实了内皮衬的保存。结论：转铁蛋白受体促进的体内基因向下腔静脉的转移导致在移植后立即产生足够的血栓调节蛋白基因表达，即使在暴露于动脉压后也能维持血栓抵抗力。尽管需要进一步的研究，但目前的结果表明针对静脉移植物疾病急性期的基因治疗的可能性。

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