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.

SUBMITTER: Song D 

PROVIDER: S-EPMC2746475 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature