Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2509-17. doi: 10.1161/ATVBAHA.111.236828.
We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.
Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.01) and lung (P<0.001). Activation of endogenous protein C following infusion of thrombin was decreased by 90% in knock-in mice compared with wild-type mice (P<0.05). Carotid artery thrombosis induced by photochemical injury occurred more rapidly in knock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes; P<0.05). No differences in serum cytokine levels were detected between knock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E-deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis.
Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.
我们试图建立一种体内研究人血栓调节蛋白抗血栓和抗炎功能的鼠模型。
生成了从鼠血栓调节蛋白基因座表达人血栓调节蛋白的基因敲入小鼠。与人血栓调节蛋白野生型小鼠相比，人血栓调节蛋白基因敲入小鼠的主动脉（P<0.01）和肺（P<0.001）中蛋白 C 的激活减少。与人血栓调节蛋白野生型小鼠相比，凝血酶输注后内源性蛋白 C 的激活减少了 90%（P<0.05）。与野生型小鼠（31±6 分钟；P<0.05）相比，光化学损伤诱导的颈总动脉血栓形成在基因敲入小鼠中发生得更快（12±3 分钟）。注射内毒素后，基因敲入和野生型小鼠之间的血清细胞因子水平没有差异。当与人载脂蛋白 E 缺陷型小鼠杂交并给予西方饮食时，基因敲入小鼠的蛋白 C 激活进一步减少，但未出现动脉粥样硬化增加。
用人类血栓调节蛋白替代鼠血栓调节蛋白表达产生的存活小鼠具有血栓形成表型，但对全身炎症或动脉粥样硬化刺激的反应不变。这种人源化动物模型将有助于在体内研究生理病理条件下人血栓调节蛋白的功能。
