title: Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice.
abstract: Although the role of systemic activation of the nuclear factor kappaB (NF-kappaB) pathway in septic coagulation has been well documented, little is known about the contribution of endothelial-specific NF-kappaB signaling in this pathologic process. Here, we used transgenic mice that conditionally overexpress a mutant I-kappaBalpha, an inhibitor of NF-kappaB, selectively on endothelium, and their wild-type littermates to define the role of endothelial-specific NF-kappaB in septic coagulation. In wild-type mice, lipopolysaccharide (LPS) challenge (5 mg/kg intraperitoneally) caused markedly increased plasma markers of coagulation, decreased plasma fibrinogen level, and widespread tissue fibrin deposition, which were abrogated by endothelial NF-kappaB blockade in transgenic mice. Endothelial NF-kappaB blockade inhibited tissue factor expression in endothelial cells, but not in leukocytes. Endothelial NF-kappaB blockade did not inhibit LPS-induced tissue factor expression in heart, kidney, and liver. Endothelial NF-kappaB blockade prevented LPS down-regulation of endothelial protein C receptor (EPCR) and thrombomodulin protein expressions, inhibited tissue tumor necrosis factor-alpha converting enzyme activity, reduced EPCR shedding, and restored plasma protein C level. Our data demonstrate that endothelial intrinsic NF-kappaB signaling plays a pivotal role in septic coagulation and suggests a link between endothelial-specific NF-kappaB activation and the impairment of the thrombomodulin-protein C-EPCR anticoagulation pathway.
authors.affiliation: Centers for Heart and Lung Research, and Immunology and Inflammation, Feinstein Institute for Medical Research, Long Island Jewish Medical Center, New Hyde Park, NY, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Song
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ye
authors.forename: Honglei
authors.initials: H
authors.lastname: Xu
authors.forename: Shu Fang
authors.initials: SF
authors.lastname: Liu
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001777:Blood Coagulation; D015153:Blotting, Western; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism*; D019446:Endotoxemia / Q000503:physiopathology*; D005340:Fibrinogen / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D018180:Thrombomodulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C080248:Procr protein, mouse; D011486:Protein C; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D051722:ADAM Proteins; D000072198:ADAM17 Protein