Open AccessSyndecan‐4 Protects the Heart From the Profibrotic Effects of Thrombin‐Cleaved Osteopontin
Author(s) -
Herum Kate M.,
Romaine Andreas,
Wang Ariel,
Melleby Arne Olav,
Strand Mari E.,
Pacheco Julian,
Braathen Bjørn,
Dunér Pontus,
Tønnessen Theis,
Lunde Ida G.,
Sjaastad Ivar,
Brakebusch Cord,
McCulloch Andrew D.,
Gomez Maria F.,
Carlson Cathrine R.,
Christensen Geir
Publication year - 2020
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.119.013518
Subject(s) - osteopontin , thrombin , medicine , fibrosis , syndecan 1 , cardiac fibrosis , extracellular matrix , pressure overload , endocrinology , microbiology and biotechnology , chemistry , biology , heart failure , biochemistry , cell , platelet , cardiac hypertrophy
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.