title: Nafamostat Mesilate Inhibits TNF-α-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production.
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-α (TNF-α). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α 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 µg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-α (3 ng/mL), and it dose dependently prevented the TNF-α-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-α-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-α-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.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Min-Woong
authors.initials: MW
authors.lastname: Kang
authors.affiliation: Department of Neurology, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Shin Kwang
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Endocrinology, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Saet-Byel
authors.initials: SB
authors.lastname: Jung
authors.affiliation: Department of Rehabilitation Medicine, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Sungju
authors.initials: S
authors.lastname: Jee
authors.affiliation: Department of Internal Medicine, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Moon
authors.affiliation: Department of Pathology, School of Medicine, Chungnam National University, Daejeon 301-721, Korea.
authors.forename: Kwang-Sun
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Korea.
authors.forename: Sang Do
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Department of physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Korea.
authors.forename: Cuk-Seong
authors.initials: CS
authors.lastname: Kim
keywords: ICAM-1; Nafamostat mesilate; Reactive oxygen species; VCAM-1; p66shc