Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A.

Blood | Jun 9, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21436072

Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII(WE)), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)-dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring antithrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII(WE) mutations within the endogenous prothrombin gene. Unlike fII-null embryos, fII(WE/WE) mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII(WT/WE) mice were viable and fertile despite a shift toward an antithrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl₃ vessel injury. More interestingly, prothrombin(WE) expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin(WE) also suppressed the development of CIA in wild-type mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes.

Pubmed ID: 21436072 RIS Download

Mesh terms: Amino Acid Substitution | Animals | Arthritis, Experimental | Hemorrhage | Humans | Mice | Mice, Mutant Strains | Mutation, Missense | Protein C | Prothrombin

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NIAMS NIH HHS, Id: P30 AR047363
  • Agency: NIAMS NIH HHS, Id: P30AR047363
  • Agency: NIAMS NIH HHS, Id: R01 AR056990
  • Agency: NHLBI NIH HHS, Id: R01 HL041002
  • Agency: NHLBI NIH HHS, Id: R01 HL041002
  • Agency: NHLBI NIH HHS, Id: R01 HL049413
  • Agency: NHLBI NIH HHS, Id: R01 HL049413
  • Agency: NHLBI NIH HHS, Id: R01 HL058141
  • Agency: NHLBI NIH HHS, Id: R01 HL073813
  • Agency: NHLBI NIH HHS, Id: R01 HL073813
  • Agency: NHLBI NIH HHS, Id: R01 HL085357
  • Agency: NHLBI NIH HHS, Id: R01 HL096126
  • Agency: NHLBI NIH HHS, Id: R44 HL095315
  • Agency: Howard Hughes Medical Institute, Id:

Mouse Genome Informatics (Data, Gene Annotation)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.