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Pontus Dunér

Assistant researcher

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Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin


  • Kate M. Herum
  • Andreas Romaine
  • Ariel Wang
  • Arne Olav Melleby
  • Mari E. Strand
  • Julian Pacheco
  • Bjørn Braathen
  • Pontus Dunér
  • Theis Tønnessen
  • Ida G. Lunde
  • Ivar Sjaastad
  • Cord Brakebusch
  • Andrew D. McCulloch
  • Maria F. Gomez
  • Cathrine R. Carlson
  • Geir Christensen

Summary, in English

Background: Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results: Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions: Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.


  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetic Complications

Publishing year







Journal of the American Heart Association





Document type

Journal article




  • Cardiac and Cardiovascular Systems


  • aortic stenosis
  • cardiac fibroblasts
  • extracellular matrix
  • left ventricular fibrosis
  • mechanical
  • myofibroblast
  • pressure overload
  • stiffness



Research group

  • Cardiovascular Research - Matrix and Inflammation in Atherosclerosis
  • Diabetic Complications


  • ISSN: 2047-9980