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Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
- Source :
- Herum, K M, Romaine, A, Wang, A, Melleby, A O, Strand, M E, Pacheco, J, Braathen, B, Dunér, P, Tønnessen, T, Lunde, I G, Sjaastad, I, Brakebusch, C, McCulloch, A D, Gomez, M F, Carlson, C R & Christensen, G 2020, ' Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin ', Journal of the American Heart Association, vol. 9, no. 3, e013518 . https://doi.org/10.1161/JAHA.119.013518, Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Publication Year :
- 2020
-
Abstract
- BackgroundPressure 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 ResultsOsteopontin 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 sequenceRGDSLAYGLRthat 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.ConclusionsThrombin‐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.
- Subjects :
- Male
Cardiac fibrosis
030204 cardiovascular system & hematology
Molecular Cardiology
Ventricular Function, Left
Syndecan 1
Extracellular matrix
stiffness
0302 clinical medicine
Fibrosis
mechanical
Osteopontin
cardiac fibroblasts
Original Research
Mice, Knockout
0303 health sciences
Ventricular Remodeling
biology
Thrombin
Remodeling
Cell biology
Cell Biology/Structural Biology
Cardiomyopathies
Cardiology and Cardiovascular Medicine
Protein Binding
medicine.drug
extracellular matrix
Collagen Type I
03 medical and health sciences
stomatognathic system
Cell Line, Tumor
medicine
Animals
Humans
030304 developmental biology
Pressure overload
business.industry
Myocardium
aortic stenosis
Aortic Valve Stenosis
pressure overload
Fibroblasts
medicine.disease
myofibroblast
Collagen Type I, alpha 1 Chain
Mice, Inbred C57BL
Disease Models, Animal
left ventricular fibrosis
biology.protein
Syndecan-4
Heparan sulfate binding
business
Cell Signalling/Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20479980
- Database :
- OpenAIRE
- Journal :
- Herum, K M, Romaine, A, Wang, A, Melleby, A O, Strand, M E, Pacheco, J, Braathen, B, Dunér, P, Tønnessen, T, Lunde, I G, Sjaastad, I, Brakebusch, C, McCulloch, A D, Gomez, M F, Carlson, C R & Christensen, G 2020, ' Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin ', Journal of the American Heart Association, vol. 9, no. 3, e013518 . https://doi.org/10.1161/JAHA.119.013518, Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
- Accession number :
- edsair.doi.dedup.....39609c571e98f8e0cf99b44a8119c03d