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Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells.
MedLine Citation:
PMID:  22819264     Owner:  NLM     Status:  Publisher    
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 50μM CORM-2 for 3hours, and stimulated with tumor necrosis factor-α (TNF-α, 10ng/ml) for an additional 0-5hours. PBMCs were pretreated with 50-100μM CORM-2 for 1hour followed by stimulating with lipopolysaccharid (LPS, 10ng/ml) for additional 0-9hours. The mRNA and protein levels were determined by RT-PCR and western blotting, respectively. RESULTS: Pretreatment with CORM-2 significantly inhibited TNF-α-induced TF and PAI-1 up-regulation in HUVECs, and LPS-induced TF expression in PBMCs. CORM-2 inhibited TNF-α-induced activation of p38 MAPK, ERK1/2, JNK, and NF-κB signaling pathways in HUVECs. CONCLUSIONS: CORM-2 suppresses TNF-α-induced TF and PAI-1 up-regulation, and MAPKs and NF-κB signaling pathways activation by TNF-α 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.
Keiko Maruyama; Eriko Morishita; Takeo Yuno; Akiko Sekiya; Hidesaku Asakura; Shigeki Ohtake; Akihiro Yachie
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-19
Journal Detail:
Title:  Thrombosis research     Volume:  -     ISSN:  1879-2472     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0326377     Medline TA:  Thromb Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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