Protection mechanism of thrombotic formation though heme oxygenase-1 in stress response

血红素加氧酶（HO）在血红素代谢中起核心作用。同时，它保护细胞免受各种氧化应激引起的损伤。对第一例HO-1缺乏症的详细分析表明，HO-1参与多种组织和器官的保护。患者的实验室数据显示高凝和高纤溶状态。为了了解高凝状态是否由HO-1缺乏直接引起，我们在体外检测了HO-1对内皮细胞的影响。第一个实验用hemin、mRNA和HO-1抗原刺激HUVEC，检测凝血/纤溶的一些参数。Hemin刺激可显著诱导HO-1的产生。即使在刺激8小时后，组织因子（TF）的产生也最低。重要的是，血红素刺激在4小时后使PAI-1的产生减少了一半以上。在第二个实验中，在TNF-a刺激HUVEC之前，hemin诱导HO-1的产生。先前暴露于血红素显著诱导HO-1的产生，但单独使用TNF-cc不能诱导HUVEC中HO-1的产生。虽然TNF-α刺激增强了TF和PAI-1的产生，但它们被先前的hemin治疗显著抑制。这些结果表明，hemin通过HO-1的产生对TF和PAI-1有抑制作用。

Heme oxygenase (HO) plays a central role heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissue and organs. Laboratory data in the patient were remarkable with hypercoagulable and heperfibrinolytic state. To see if the hypercoagulable state is directly caused by HO-1 deficiency, we examined the effect of HO-1 in endothelial cells in vitro.In the first experiment, HUVEC was stimulated with hemin and mRNA and antigens for HO-1 and some of the parameters of coagulation/fibrinolysis were examined. Hemin stimulation induced significant levels of HO-1 production. Tissue factor (TF) production was minimum even after 8hrs of stimulation. Importantly, hemin stimulation reduced PAI-1 production more than half after 4hrs. In the second experiment, HO-1 production was induced by hemin prior to stimulation of HUVEC with TNF-a. Prior exposure to hemin induced significantly HO-1 production, but TNF-cc alone could not induce HO-1 in HUVEC. Although stimulation with TNF-α enhanced productions of both TF and PAI-1, they were significantly inhibited by prior treatment with hemin. These results indicate that hemin exert inhibitory effect on TF and PAI-1 through HO-1 production.