Nafamostat Mesilate Inhibits TNF-alpha-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production.
10.4196/kjpp.2015.19.3.229
- Author:
Min Woong KANG
1
;
Hee Jung SONG
;
Shin Kwang KANG
;
Yonghwan KIM
;
Saet Byel JUNG
;
Sungju JEE
;
Jae Young MOON
;
Kwang Sun SUH
;
Sang Do LEE
;
Byeong Hwa JEON
;
Cuk Seong KIM
Author Information
1. Department of Thoracic and Cardiovascular Surgery, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
- Publication Type:Original Article
- Keywords:
ICAM-1;
Nafamostat mesilate;
p66shc;
Reactive oxygen species;
VCAM-1
- MeSH:
Asia;
Endothelial Cells*;
Extracorporeal Circulation;
Human Umbilical Vein Endothelial Cells;
Humans;
Intercellular Adhesion Molecule-1;
Membranes;
Mesylates*;
Monocytes;
Oxidative Stress;
Oxygen;
p38 Mitogen-Activated Protein Kinases;
Phosphorylation;
Protein Kinases;
Reactive Oxygen Species*;
Renal Replacement Therapy;
Risk Factors;
Serine Proteases;
Superoxides;
Tumor Necrosis Factor-alpha;
Up-Regulation;
Vascular Cell Adhesion Molecule-1;
Vascular Diseases
- From:The Korean Journal of Physiology and Pharmacology
2015;19(3):229-234
- CountryRepublic of Korea
- Language:English
-
Abstract:
Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-alpha (TNF-alpha). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-alpha for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 microg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-alpha (3 ng/mL), and it dose dependently prevented the TNF-alpha-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-alpha-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-alpha-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.
