title: Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.
abstract: OBJECTIVE
  We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors: Thomas J
authors: TJ
authors: Raife
authors: Denis M
authors: DM
authors: Dwyre
authors: Jeff W
authors: JW
authors: Stevens
authors: Rochelle A
authors: RA
authors: Erger
authors: Lorie
authors: L
authors: Leo
authors: Katina M
authors: KM
authors: Wilson
authors: Jose A
authors: JA
authors: Fernández
authors: Jennifer
authors: J
authors: Wilder
authors: Hyung-Suk
authors: HS
authors: Kim
authors: John H
authors: JH
authors: Griffin
authors: Nobuyo
authors: N
authors: Maeda
authors: Steven R
authors: SR
authors: Lentz
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004195:Disease Models, Animal; D004731:Endotoxins / Q000494:pharmacology; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism; D013045:Species Specificity; D018180:Thrombomodulin / Q000235:genetics* / Q000502:physiology*; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D004731:Endotoxins; C546931:THBD protein, human; D018180:Thrombomodulin; D011493:Protein Kinase C