Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Pontus Dunér

Assistant researcher

Default user image.

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

Author

  • 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.

Department/s

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

Publishing year

2020-02-04

Language

English

Pages

013518-013518

Publication/Series

Journal of the American Heart Association

Volume

9

Issue

3

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Cardiac and Cardiovascular Systems

Keywords

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

Status

Published

Research group

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

ISBN/ISSN/Other

  • ISSN: 2047-9980