Antithrombin deficiency in mice results in embryonic lethality and thrombotic tendency.

小鼠抗凝血酶缺乏会导致胚胎死亡和血栓形成倾向。

• 批准号: 13470203
• 负责人: TAKAMATU Junki
• 金额: $ 10.18万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470203/
• 关键词: Antithrombin; Sindecan; Thrombosis; recombination; Knock owt; LPS; antithrombin; Svndecan; Polymerase chain reaction; platelet; thrombosis; Knock out mouse

Antithrombin is a plasma protease inhibitor that inhibits thrombin and contributes to the maintenance of blood fluidity. Using targeted gene disruption, we investigated the role of antithrombin in embryogenesis. Mating mice heterozygous for antithrombin gene (ATIII) disruption, ATIII (+/-), yielded the expected Mendelian distribution of genotypes until 14.5 gestational days (gd). However, approximately 70% of the ATIII (-/-) embryos at 15.5 gd and 100% at 16.5 gd had died and showed extensive subcutaneous hemorrhage. Histological examination of those embryos revealed extensive fibrin (ogen) deposition in the myocardium and liver, but not in the brain or lung. Furthermore, no apparent fibrin (ogen) deposition was detected in the extensive hemorrhagic region, suggesting that fibrinogen might be decreased due to consumptive coagulopathy and/or liver dysfunction. These finding suggest that antithrombin is essential for embryonic survival and that it plays an important role in regulation of … More blood coagulaation in the myocardium and liver. In contrast, heterozygous AT-deficient mice with 50% AT activities have not shown spontaneous thromboembolic episodes To demonstrate a thrombotic tendency in heterzygous AT deficiency, we challenged heterozygous AT- deficient mice (AT+/-mice) with the administration of lipopolysaccharide (LPS) or with restraint stress by immobilization. LPS injection markedly induced fibrin deposition in the kidney glomeruli, myocardium, and liver sinusoids in AT+/-mice compared with wild-type mice (AT+/+mice). Restraint stress tests were performed by placing mice in 50-mL conical centrifuge tubes for 20 hours. Fibrin deposition was observed in the kidney of AT+/+and AT+/-mice, but AT+/- mice exhibited more extensive fibrin deposition than AT+/+ mice. After prophylactic administration of human AT concentrates to increase plasma AT activities of AT+/-mice, LPS-induced fibrin deposition was effectively prevented. These results suggest that heterozygous AT deficiency is significantly associated with a tendency toward thrombosis formatin in the kidney. The AT+/-mouse thus is a useful model for studying the effect of environmental or genetic risk factors on thrombogenesis. Less

抗凝血酶是一种血浆蛋白酶抑制剂，可抑制凝血酶并有助于维持血液流动性。利用靶向基因破坏，我们研究了抗凝血酶在胚胎发生中的作用。抗凝血酶基因（ATIII）破坏杂合子（ATIII（+/-））交配小鼠产生预期的孟德尔基因型分布，直至妊娠14.5天（gd）。然而，15.5 gd时约70%的ATIII（-/-）胚胎和16.5 gd时100%的ATIII（-/-）胚胎死亡，并显示出广泛的皮下出血。对这些胚胎的组织学检查显示，心肌和肝脏中有大量纤维蛋白（原）沉积，但脑或肺中没有。此外，在广泛出血区域未检测到明显的纤维蛋白（原）沉积，表明纤维蛋白原可能由于消耗性凝血病和/或肝功能障碍而降低。这些发现表明抗凝血酶对胚胎存活是必需的，并且在调节胚胎发育中起重要作用。 ...更多信息 心肌和肝脏中的血液凝固。相比之下，具有50%AT活性的杂合AT缺陷小鼠未显示自发血栓栓塞发作。为了证明杂合AT缺陷中的血栓形成倾向，我们用脂多糖（LPS）给药或通过固定的束缚应激来攻击杂合AT缺陷小鼠（AT+/-小鼠）。与野生型小鼠（AT+/+小鼠）相比，LPS注射显著诱导AT+/-小鼠肾小球、心肌和肝窦中的纤维蛋白沉积。通过将小鼠置于50 mL锥形离心管中20小时进行束缚应激试验。在AT+/+和AT+/-小鼠的肾脏中观察到纤维蛋白沉积，但AT+/-小鼠比AT+/+小鼠表现出更广泛的纤维蛋白沉积。在预防性给予人AT浓缩物以增加AT+/-小鼠的血浆AT活性后，有效地防止了LPS诱导的纤维蛋白沉积。这些结果表明，杂合子AT缺陷与肾脏血栓形成的倾向显著相关。因此，AT+/-小鼠是研究环境或遗传风险因素对血栓形成的影响的有用模型。少

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