Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells
Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells
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DOI：
10.1016/j.thromres.2012.07.002
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发表时间：
2012-09-01
影响因子：
7.5
通讯作者：
Yachie, Akihiro
中科院分区：
文献类型：
--
作者：
Maruyama, Keiko;Morishita, Eriko;Yachie, Akihiro
简介：血红素加氧酶-1（HO-1）是血红素转化为胆绿素、游离铁和一氧化碳的限速酶。第一例HO-1缺乏症显示凝血和纤溶系统异常。因此，HO-1或HO-1产物，如CO，可能调节凝血和纤溶系统。本研究探讨是否三羰基二氯钌（II）二聚体（CORM-2），释放CO，调节组织因子（TF）和纤溶酶原激活物抑制剂1型（派-1）在人脐静脉内皮细胞（HUVECs）的表达，和TF在外周血单核细胞（PBMC）的表达。此外，我们研究了CO发挥其effects.Materials and Methods的机制：HUVECs预处理50 μ M CORM-2 3小时，并刺激与肿瘤坏死因子-α（TNF-α，10 ng/ml）为额外的0-5小时。PBMC用50-100 μ M CORM-2预处理1小时，然后用脂多糖（LPS，10 ng/ml）刺激0-9小时。结果：CORM-2预处理可显著抑制TNF-α诱导的HUVECs TF和派-1表达上调及LPS诱导的PBMC TF表达上调。CORM-2抑制TNF-α诱导的HUVECs中p38 MAPK、ERK 1/2、JNK和NF-κ B信号通路的激活。结论：CORM-2抑制TNF-α诱导的HUVECs中TF和派-1的上调，以及TNF-α对MAPK和NF-κ B信号通路的激活。CORM-2抑制LPS诱导的PBMC中TF上调。因此，我们设想CORM-2的抗血栓形成活性可用作治疗各种炎症状况的药剂。(C)2012爱思唯尔有限公司保留所有权利。
Introduction: Heme oxygenase-1 (HO-1) is the rate limiting enzyme that catalyzes the conversion of heme into biliverdin, free iron, and carbon monoxide (CO). The first human case of HO-1 deficiency showed abnormalities in blood coagulation and the fibrinolytic system. Thus, HO-1 or HO-1 products, such as CO, might regulate coagulation and the fibrinolytic system. This study examined whether tricarbonyldichlororuthenium (II) dimer (CORM-2), which liberates CO, modulates the expression of tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) in human umbilical vein endothelial cells (HUVECs), and TF expression in peripheral blood mononuclear cells (PBMCs). Additionally, we examined the mechanism by which CO exerts its effects.Materials and Methods: HUVECs were pretreated with 50 mu M CORM-2 for 3 hours, and stimulated with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) for an additional 0-5 hours. PBMCs were pretreated with 50-100 mu M CORM-2 for 1hour followed by stimulating with lipopolysaccharid (LPS, 10 ng/ml) for additional 0-9 hours. The mRNA and protein levels were determined by RT-PCR and western blotting, respectively.Results: Pretreatment with CORM-2 significantly inhibited TNF-alpha-induced TF and PAI-1 up-regulation in HUVECs, and LPS-induced TF expression in PBMCs. CORM-2 inhibited TNF-alpha-induced activation of p38 MAPK, ERK1/2, JNK, and NF-kappa B signaling pathways in HUVECs.Conclusions: CORM-2 suppresses TNF-alpha-induced TF and PAI-1 up-regulation, and MAPKs and NF-kappa B signaling pathways activation by TNF-alpha in HUVECs. CORM-2 suppresses LPS-induced TF up-regulation in PBMCs. Therefore, we envision that the antithrombotic activity of CORM-2 might be used as a pharmaceutical agent for the treatment of various inflammatory conditions. (C) 2012 Elsevier Ltd. All rights reserved.