Heparin cofactor H inhibits arterial thrombosis after endothelial injury
Heparin cofactor H inhibits arterial thrombosis after endothelial injury
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DOI：
10.1172/jci13432
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Tollefsen, DM
中科院分区：
文献类型：
--
作者：
He, L;Vicente, CP;Tollefsen, DM
肝素辅助因子II （HCII）是一种血浆蛋白，可在硫酸皮肤素、硫酸肝素或肝素存在时迅速抑制凝血酶。HCII被认为可以调节凝血或参与炎症、动脉粥样硬化和伤口修复等过程。为了研究HCII的生理功能，在胚胎干细胞中，通过同源重组，删除了约2kb的小鼠HCII基因，编码该蛋白的n端一半。F-1 HCII-/-动物的杂交以预期的孟德尔频率产生HC11（-/-）后代。生化分析证实HCII-/-动物血浆中不存在皮肤硫酸酯依赖性凝血酶抑制。HCII-/-动物杂交产生的产仔大小与杂合交配所得的产仔大小相似。在1岁时，缺乏hci的动物在体重和存活率方面与野生型同伴基本没有区别，并且它们似乎没有自发性血栓形成或其他形态异常。然而，与野生型动物相比，它们在光化学诱导的内皮细胞损伤后，颈动脉血栓闭塞的时间明显缩短。这种异常可以通过输注纯化的HCII而不是卵清蛋白来纠正。这些观察结果表明，HCII可能抑制动脉循环中的血栓形成。
Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin rapidly in the presence of dermatan sulfate, heparan sulfate, or heparin. HCII has been proposed to regulate coagulation or to participate in processes such as inflammation, atherosclerosis, and wound repair. To investigate the physiologic function of HCII, about 2 kb of the mouse HCII gene, encoding the N-terminal half of the protein, was deleted by homologous recombination in embryonic stem cells. Crosses of F-1 HCII-/- animals produced HC11(-/-) offspring at the expected mendelian frequency. Biochemical assays confirmed the absence of dermatan sulfate-dependent thrombin inhibition in the plasma of HCII-/- animals. Crosses of HCII-/- animals produced litters similar in size to those obtained from heterozygous matings. At 1 year of age, HCII-deficient animals were grossly indistinguishable from their wild-type littermates in weight and survival, and they did not appear to have spontaneous thrombosis or other morphologic abnormalities. In comparison withwild-type animals, however, they demonstrated a significantly shorter time to thrombotic occlusion of the carotid artery after photochemically induced endothelial cell injury. This abnormality was corrected by infusion of purified HCII but not ovalbumin. These observations suggest that HCII might inhibit thrombosis in the arterial circulation.