Dataset Information

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

ABSTRACT: We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.01) and lung (P<0.001). Activation of endogenous protein C following infusion of thrombin was decreased by 90% in knock-in mice compared with wild-type mice (P<0.05). Carotid artery thrombosis induced by photochemical injury occurred more rapidly in knock-in mice (12±3 minutes) than in wild-type mice (31±6 minutes; P<0.05). No differences in serum cytokine levels were detected between knock-in and wild-type mice after injection of endotoxin. When crossed with apolipoprotein E-deficient mice and fed a Western diet, knock-in mice had a further decrease in protein C activation but did not exhibit increased atherosclerosis.Expression of human thrombomodulin in place of murine thrombomodulin produces viable mice with a prothrombotic phenotype but unaltered responses to systemic inflammatory or atherogenic stimuli. This humanized animal model will be useful for investigating the function of human thrombomodulin under pathophysiological conditions in vivo.

SUBMITTER: Raife TJ

PROVIDER: S-EPMC3202707 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

Raife Thomas J TJ Dwyre Denis M DM Stevens Jeff W JW Erger Rochelle A RA Leo Lorie L Wilson Katina M KM Fernández Jose A JA Wilder Jennifer J Kim Hyung-Suk HS Griffin John H JH Maeda Nobuyo N Lentz Steven R SR

Arteriosclerosis, thrombosis, and vascular biology 20111101 11

<h4>Objective</h4>We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.<h4>Methods and results</h4>Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.01) and lung (P<0.001). Activation of endogenous protein C following infusion of thrombin was d ...[more]

PMID: 21885846

Similar Datasets

Project description:It has been demonstrated that thrombomodulin (TM) serves an important role in the formation of deep venous thrombosis (DVT) and is regarded to be a marker that can be used to measure vascular endothelial cell damage. However, how TM levels change during DVT evolution has not yet been well understood. The current study aimed to investigate the dynamic changes of TM during the evolution of DVT and explore the possible mechanisms behind these. A total of 48 patients newly diagnosed with DVT and 23 matched healthy controls were enrolled in the present study, and their plasma TM levels were examined and compared. In addition, a DVT model was established using Sprague-Dawley rats via the 'stenosis' method. The thrombi size, histopathologic changes and expression of TM and NF-κB in plasma and venous endothelium were measured at 9 different time points (1, 4, 6, 12 and 24 h, and at 3, 7, 14 and 21 days). Finally, the effect of inhibiting the activation of NF-κB on TM was investigated using pyrrolidine dithiocarbamate (PDTC), which is a potent inhibitor of the NF-κB pathway. The results of the current study indicated that the mean level of plasma TM in patients with DVT was significantly increased compared with healthy controls. In addition, thrombi size (clot length and weight), TM and NF-κB expression in the animal model plasma exhibited three distinct periods (1-12, 24 h-day 7 and 14-21) of markedly different results between periods. Immunofluorescence results confirmed the co-localization of TM and NF-κB in endothelial cells. In addition, it was indicated that the expression of TM in the endothelium of DVT models was upregulated compared with the control, while NF-κB was significantly downregulated. Following the administration of PDTC, the level of NF-κB and TM in the plasma were decreased significantly dose-dependently. The results of the current study suggested that TM was involved in the evolution of DVT and may be used as a dynamic biomarker to measure disease activity. Furthermore, the expression of TM during the evolution of DVT was indicated to be associated with the NF-κB signaling pathway.

Dataset Information

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

Publications

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets