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Regulation of endothelial cell function by transgene expression and development of gene therapy for vascular diseases

通过转基因表达调节内皮细胞功能和开发血管疾病基因治疗

基本信息

批准号：
14570689
负责人：
MIMURO Jun
金额：
$ 2.56万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14570689/
关键词：
endothelial cell viral vector gene therapy PAI-1 VEGF 血管内皮細胞血管新生 Vascular endothelial growth factor Angiopoietin 1 Prostacyclin

项目摘要

We have hypothesized that there might be a kind of cross-talk between plasminogen activator-plasmin dependent fibrinolytic system and granulocyte-derived elastase dependent one, according to the following observations : 1,congenital plasminogen-deficient patients have no intravascular thrombophilic episodes. The granulocyte-derived elastase level of these patients in plasma is 10-100 times higher than that of the normal. Moreover, infusion of purified plasminogen decreases the level to a normal range. 2, plasminogen activator-plasmin dependent fibrinolytic system is supposed to be shutdown by remarkable increase of plasminogen activator inhibitor -1 in patient with disseminated intravascular coagulation associated with severe sepsis. Using ELISA system employing a monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrin, we found that the elastase fibrin-digests were mostly elevated in these patients.To support this hypothesis, we used plasminogen-deficient mice (KO mice) with synthetic elastase inhibitor. After the age of 7 weeks, 19% of KO mice develop rectal prolapse due to intravascular thrombosis in microcirculation. Unexpectedly, administration of elastase inhibitor protected KO mice from rectal prolapse. In addition, the amount of leukocyte infiltration and a fibrin deposit in the lung after lipopolysacharride loading were also decreased by concomitant elastase inhibition. These results suggest a cross-talk between two systems is more complicated and much more needs to be learned about the role of elastase in relation to alternative fibrinolytic system.

根据以下观察结果，我们推测纤溶酶原激活物-纤溶酶依赖的纤溶系统和粒细胞源性弹性蛋白酶依赖的纤溶系统之间可能存在某种串扰：1、先天性纤溶酶原缺乏患者无血管内血栓形成。这些患者血浆中的粒细胞衍生弹性蛋白酶水平比正常人高10-100倍。此外，输注纯化的纤溶酶原可将水平降低至正常范围。2、严重脓毒症患者血浆纤溶酶原激活物抑制物-1水平明显升高，可能是纤溶酶原激活物-纤溶酶依赖性纤溶系统关闭的原因。我们用特异于人纤维蛋白中粒细胞衍生的弹性蛋白酶D片段的单克隆抗体进行ELISA检测，发现这些患者的弹性蛋白酶纤维蛋白酶活性大多升高，为了支持这一假设，我们用合成弹性蛋白酶抑制剂的纤溶酶原缺陷小鼠（KO小鼠）。7周龄后，19%的KO小鼠由于微循环中的血管内血栓形成而发生直肠脱垂。出乎意料的是，给予弹性蛋白酶抑制剂保护KO小鼠免于直肠脱垂。此外，脂多糖负荷后肺中白细胞浸润和纤维蛋白存款的量也通过伴随的弹性蛋白酶抑制而减少。这些结果表明，两个系统之间的串扰是更复杂的，需要更多的了解弹性蛋白酶的作用，替代纤维蛋白溶解系统。