Roles of Coagulation Proteases and PARs (Protease-Activated Receptors) in Mouse Models of Inflammatory Diseases

Jens J Posma, Steven P Grover, Yohei Hisada, A Phillip Owens, Silvio Antoniak, Henri M Spronk, Nigel Mackman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation. In addition, coagulation proteases activate cells by cleavage of PARs (protease-activated receptors), including PAR1 and PAR2. Direct oral anticoagulants have recently been developed to specifically inhibit the coagulation proteases FXa (factor Xa) and thrombin. Administration of these inhibitors to wild-type mice can be used to determine the roles of FXa and thrombin in different inflammatory diseases. These results can be compared with the phenotypes of mice with deficiencies of either Par1 (F2r) or Par2 (F2rl1). However, inhibition of coagulation proteases will have effects beyond reducing PAR signaling, and a deficiency of PARs will abolish signaling from all proteases that activate these receptors. We will summarize studies that examine the roles of coagulation proteases, particularly FXa and thrombin, and PARs in different mouse models of inflammatory disease. Targeting FXa and thrombin or PARs may reduce inflammatory diseases in humans.

Original languageEnglish
Pages (from-to)13-24
Number of pages12
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume39
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

  • DIET-INDUCED OBESITY
  • DIRECT THROMBIN INHIBITOR
  • FACTOR GENE-EXPRESSION
  • FACTOR XA INHIBITOR
  • FATTY LIVER-DISEASE
  • INNATE IMMUNE-RESPONSE
  • ISCHEMIA-REPERFUSION INJURY
  • MYOCARDIAL ISCHEMIA/REPERFUSION INJURY
  • SICKLE-CELL-DISEASE
  • TISSUE-FACTOR
  • anticoagulants
  • blood coagulation
  • inflammation
  • models, animal
  • thrombin

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