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Blood. 2009 Sep 17;114(12):2521-9. doi: 10.1182/blood-2009-02-205914. Epub 2009 Jul 20.

Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice.

Author information

1
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.

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.

PMID:
19620400
PMCID:
PMC2746475
DOI:
10.1182/blood-2009-02-205914
[Indexed for MEDLINE]
Free PMC Article

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