Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin
(2020) In Journal of the American Heart Association 9(3). p.013518-013518- Abstract
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... (More)
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.
(Less)
- author
- Herum, Kate M.
; Romaine, Andreas
; Wang, Ariel
; Melleby, Arne Olav
; Strand, Mari E.
; Pacheco, Julian
; Braathen, Bjørn
; Dunér, Pontus
LU
; Tønnessen, Theis
; Lunde, Ida G.
; Sjaastad, Ivar
; Brakebusch, Cord
LU
; McCulloch, Andrew D.
; Gomez, Maria F.
LU
; Carlson, Cathrine R.
and Christensen, Geir
(Less) - organization
- publishing date
- 2020-02-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- aortic stenosis, cardiac fibroblasts, extracellular matrix, left ventricular fibrosis, mechanical, myofibroblast, pressure overload, stiffness
- in
- Journal of the American Heart Association
- volume
- 9
- issue
- 3
- pages
- 013518 - 013518
- publisher
- Wiley-Blackwell
- external identifiers
-
- pmid:32000579
- scopus:85078712084
- ISSN
- 2047-9980
- DOI
- 10.1161/JAHA.119.013518
- language
- English
- LU publication?
- yes
- id
- 5ae436c1-d03e-431c-b7c3-8f75a19dc173
- date added to LUP
- 2020-02-11 14:01:46
- date last changed
- 2024-04-17 03:49:00
@article{5ae436c1-d03e-431c-b7c3-8f75a19dc173,
abstract = {{<p>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.</p>}},
author = {{Herum, Kate M. and Romaine, Andreas and Wang, Ariel and Melleby, Arne Olav and Strand, Mari E. and Pacheco, Julian and Braathen, Bjørn and Dunér, Pontus and Tønnessen, Theis and Lunde, Ida G. and Sjaastad, Ivar and Brakebusch, Cord and McCulloch, Andrew D. and Gomez, Maria F. and Carlson, Cathrine R. and Christensen, Geir}},
issn = {{2047-9980}},
keywords = {{aortic stenosis; cardiac fibroblasts; extracellular matrix; left ventricular fibrosis; mechanical; myofibroblast; pressure overload; stiffness}},
language = {{eng}},
month = {{02}},
number = {{3}},
pages = {{013518--013518}},
publisher = {{Wiley-Blackwell}},
series = {{Journal of the American Heart Association}},
title = {{Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin}},
url = {{http://dx.doi.org/10.1161/JAHA.119.013518}},
doi = {{10.1161/JAHA.119.013518}},
volume = {{9}},
year = {{2020}},
}