title: Factor Xa inhibits HMGB1-induced septic responses in human umbilical vein endothelial cells and in mice.
abstract: Nuclear DNA-binding protein high mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis. Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, and it influences cell signalling in various cell types by activating protease-activated receptors (PARs). However, the effect of FXa on HMGB1-induced inflammatory response has not been studied. First, we addressed this issue by monitoring the effects of post-treatment with FXa on lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment with FXa was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. FXa also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. In addition, FXa inhibited the production of tumour necrosis factor-α and interleukin (IL)-1β. FXa also facilitated the downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that FXa may be regarded as a candidate therapeutic agent for treating vascular inflammatory diseases by inhibiting the HMGB1 signalling pathway.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: Jong-Sup Bae, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Republic of Korea, Tel.: +82 53 950 8570, Fax: +82 53 950 8557, E-mail: baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D002448:Cell Adhesion; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000097:blood; D015536:Down-Regulation; D017097:Electric Impedance; D015951:Factor Xa / Q000737:chemistry*; D024243:HMGB1 Protein / Q000097:blood*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010539:Permeability; D018805:Sepsis / Q000097:blood*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases; D015951:Factor Xa
keywords: FXa; HMGB1; sepsis; vascular inflammation