Journal
THROMBOSIS RESEARCH
Volume 130, Issue 3, Pages E188-E193Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2012.07.002
Keywords
CORM-2; TF; PAI-1; HUVECs
Categories
Funding
- Ministry of Education, Science, Sports and Culture of Japan
- Kanazawa University, Kanazawa
- Mitani Inc., Kanazawa
- Grants-in-Aid for Scientific Research [24590684, 24790549] Funding Source: KAKEN
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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.
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