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

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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.