DOCSLIB.ORG

SPARC Preserves Endothelial Glycocalyx Integrity, and Protects

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SPARC Preserves Endothelial Glycocalyx Integrity, and Protects University of Birmingham SPARC preserves endothelial glycocalyx integrity, and protects against adverse cardiac inflammation and injury during viral myocarditis Rienks, Marieke; Carai, Paolo; Teeffelen, Jurgen van; Eskens, Bart; Verhesen, Wouter; Hemmeryckx, Bianca; Johnson, Daniel M.; Leeuwen, Rick van; Jones, Elizabeth A.; Heymans, Stephane; Papageorgiou, Anna-Pia DOI: 10.1016/j.matbio.2018.04.015 License: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Rienks, M, Carai, P, Teeffelen, JV, Eskens, B, Verhesen, W, Hemmeryckx, B, Johnson, DM, Leeuwen, RV, Jones, EA, Heymans, S & Papageorgiou, A-P 2018, 'SPARC preserves endothelial glycocalyx integrity, and protects against adverse cardiac inflammation and injury during viral myocarditis', Matrix Biology, pp. 21-34. https://doi.org/10.1016/j.matbio.2018.04.015 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 30. Sep. 2021 Article SPARC preserves endothelial glycocalyx integrity, and protects against adverse cardiac inflammation and injury during viral myocarditis Marieke Rienks a,b, Paolo Carai b, Jurgen van Teeffelen d, Bart Eskens d, Wouter Verhesen a, Bianca Hemmeryckx c, Daniel M. Johnson b, Rick van Leeuwen b, Elizabeth A. Jones c, Stephane Heymans b,c,e,† and Anna-Pia Papageorgiou b,c,† a - Cardiovascular Department, King's College London, United Kingdom b - Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, The Netherlands c - Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU, Leuven, Belgium d - Department of Physiology, Maastricht University, The Netherlands e - Netherlands Heart Institute, ICIN, Utrecht, The Netherlands Correspondence to Marieke Rienks: Cardiovascular Research Institute Maastricht, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands. [email protected]. https://doi.org/10.1016/j.matbio.2018.04.015 Abstract Myocardial damage as a consequence of cardiotropic viruses leads to a broad variety of clinical presentations and is still a complicated condition to diagnose and treat. Whereas the extracellular matrix protein Secreted Protein Acidic and Rich in Cysteine or SPARC has been implicated in hypertensive and ischemic heart disease by modulating collagen production and cross-linking, its role in cardiac inflammation and endothelial function is yet unknown. Absence of SPARC in mice resulted in increased cardiac inflammation and mortality, and reduced cardiac systolic function upon coxsackievirus-B3 induced myocarditis. Intra-vital microscopic imaging of the microvas- culature of the cremaster muscle combined with electron microscopic imaging of the microvasculature of the cardiac muscle uncovered the significance of SPARC in maintaining endothelial glycocalyx integrity and subsequent barrier properties to stop inflammation. Moreover, systemic administration of recombinant SPARC restored the endothelial glycocalyx and consequently reversed the increase in inflammation and mortality observed in SPARC KO mice in response to viral exposure. Reducing the glycocalyx in vivo by systemic administration of hyaluronidase, an enzyme that degrades the endothelial glycocalyx, mimicked the barrier defects found in SPARC KO mice, which could be restored by subsequent administration of recombinant SPARC. In conclusion, the secreted glycoprotein SPARC protects against adverse cardiac inflammation and mortality by improving the glycocalyx function and resulting endothelial barrier function during viral myocarditis. © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction biopsy [2], the true incidence is still not precisely known yet, estimating 1 to 10 cases per 100,000 Myocarditis is defined as inflammation of the heart persons each year. muscle and can be caused by a variety of infectious Not only can acute viral myocarditis lead to sudden and non-infectious illnesses. Amongst the infectious cardiac arrest [5], but it is also a major cause of causes, viruses are supposedly the most frequent congestive heart failure [6] and in some cases even pathogens affecting the myocardium. The broad requires cardiac transplantation. Responsible cardi- variety of clinical presentations, make viral myocarditis otropic viruses, such as the entero-coxsackie B a complicated condition to diagnose and treat. Despite viruses, can induce this severe cardiac inflammation combining the standardized criteria for histological in susceptible patients, resulting in heart failure and diagnosis of myocarditis [1] with endomyocardial possibly sudden death. This form of heart disease is 0022-2836/© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Matrix Biol. (2018) 74,21–34 22 SPARC preserves endothelial glycocalyx integrity particularly devastating as it affects previously healthy [14,15]. The endothelial glycocalyx does not just young adults. In spite of our better understanding of infer the luminal lining of the endothelium but in the causative cardiotropic viruses and consecutive fact encapsulates endothelial cells and expand immunological mechanisms that contribute to the towards the endothelial basement membrane [14]. development of cardiac dysfunction [7], diagnosis and Therefore, we investigated the role of the endothe- treatment for myocarditis are still poor. Elucidating the lial glycocalyx in regulating inflammation in viral underlying mechanisms of enhanced or sustained myocarditis in this study with a specific focus on cardiac inflammation can facilitate the development ECM protein Secreted Protein Acidic and Rich in of new specific therapies for viral myocarditis. Cysteine (SPARC). The cardiac extracellular matrix (ECM), comprised SPARC has been shown to regulate fibroblast of proteoglycans, glycoproteins and glycosamino- function in connective tissue [16–19] as well as glycans [8], plays an important role in intercellular tumour development and progression [20,21], bone communication during cardiac disease [9,10]. Since homeostasis and repair [22], angiogenesis [23] and inflammation and heart failure reciprocally trigger cardiac ageing [18,24,25]. Moreover, both in vitro one another [11], we speculated that ECM proteins studies and in vivo murine oncology studies have may trigger heart failure development by potentiating recognized the increased vascular permeability in the immune response [12,13]. When addressing the the absence of SPARC [26,27], however the mech- interaction of the immune system and the ECM in anisms by which SPARC may influence vascular cardiac disease however, the prominent vascular permeability are still unclear. Where SPARC has gatekeeper known as the endothelial glycocalyx is been recognized for its fundamental roles as an often overlooked. This while the endothelial glycoca- adhesive component of the ECM, no attention has lyx is comprised of similar proteoglycans, glycopro- been given to the extracellular lining of the endothe- teins and glycosaminoglycans to the cardiac ECM lium as a possible immune-regulating structure and is known to regulate inflammation, vascular housing SPARC [14]. As the expression of SPARC permeability, coagulation and mechanotransduction is low during normal post-natal life but dramatically A B C D CD45 Viral myocarditis m R N A ).u WT 20 4 %) 100 %) *** ( a . ( KO a ( 15 3 i v a l H 5 s i o n D V a r e C D 4 AP 10 2 v 50 r s S u e G /3 e x p r o f L 5 1 VB C 0 0 0 WT KO WT KO 0 20 40 60 80 Time (days) E F Sham Viral myocarditis ) ) 300000 ) 300000 600000 o c a r d i u m 600000 d WT n=6 WT n=5 WT n=5 i u m WT n=5 ) o o o d KO n=5 KO n=5 lb KO n=3 0.08 KO n=4 r d olb s ( 400000 c a 200000 200000 400000 0.08 s ( t y o * m y n e n t e m 200000 ( 100000 v 100000 200000 ( # e n t s # e v s n t * v e 0 v e 0 0 0 slle B - c e l l s e s sll e s s e sll T - c e l l s s u l o c y t e s t e s sl sl s - c e l l s e s sll s s # e s e s s l l T - c e l l t e - c e l l l e ty c e l # t e c y t t e + c e t c y t D 4 5 + c e c y t c e e e c y y c y -T y c- y n o c c n o c B- u l o c o n o c o n o c o T lu B o M o n o B o + + C D 4 5 l n C D 4 5 5 o o G r a n u m o n D 4 r a n n m a M a M M r ih r ih C C G G G C C 6 L y 6 y L Fig.
Load more

Recommended publications
  • Emerging Views of Heparan Sulfate Glycosaminoglycan Structure
    chain contains a b-D-glucosamine linked to an uronic acid, which can be one of two C5 epimers, either a-L-iduronic or b-D-glucuronic acid. Other than the C5 Emerging Views of Heparan Sulfate position of the uronic acid, HLGAGs Glycosaminoglycan Structure/Activity vary in their chain length, that is, the number of disaccharide repeat units, and Relationships Modulating Dynamic degree of sulfation and acetylation of each disaccharide unit. O-sulfation of the Biological Functions disaccharide repeat can occur at the 2-O Zachary Shriver, Dongfang Liu, and Ram Sasisekharan* position of the uronic acid and the 6-O and 3-O positions of the glucosamine. Thus, for a given disaccharide unit within an HSGAG structure, each site is Heparan sulfate glycosaminoglycans (HSGAGs) are an important subset either sulfated or unsubstituted, creat- of complex polysaccharides that represent the third major class of biopoly- ing eight possible combinations. In ad- mer, along with polynucleic acids and polypeptides. However, the impor- dition, as mentioned above, there are two possibilities for the uronic acid com- tance of HSGAGs in biological processes is underappreciated because of a ponent of each disaccharide unit, that lack of effective molecular tools to correlate specific structures with func- is, either iduronic acid or glucuronic tions. Only recently have significant strides been made in understanding acid, giving rise to a total of 16 different the steps of HSGAG biosynthesis that lead to the formation of unique possible disaccharide combinations. Fi- nally, the N-position of the glucosamine structures of functional importance. Such advances now create possibili- can be sulfated, acetylated, or unsubsti- ties for intervening in numerous clinical situations, creating much-needed tuted (three possible states).
    [Show full text]
  • Demystifying Heparan Sulfate–Protein Interactions
    UC San Diego UC San Diego Previously Published Works Title Demystifying heparan sulfate-protein interactions. Permalink https://escholarship.org/uc/item/0wj6876w Journal Annual review of biochemistry, 83(1) ISSN 0066-4154 Authors Xu, Ding Esko, Jeffrey D Publication Date 2014 DOI 10.1146/annurev-biochem-060713-035314 Peer reviewed eScholarship.org Powered by the California Digital Library University of California BI83CH06-Esko ARI 3 May 2014 10:35 Demystifying Heparan Sulfate–Protein Interactions Ding Xu and Jeffrey D. Esko Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093; email: [email protected], [email protected] Annu. Rev. Biochem. 2014. 83:129–57 Keywords First published online as a Review in Advance on heparin-binding protein, glycosaminoglycan, proteoglycan, March 6, 2014 glycan–protein interaction, heparan sulfate–binding domain, The Annual Review of Biochemistry is online at oligomerization biochem.annualreviews.org Annu. Rev. Biochem. 2014.83:129-157. Downloaded from www.annualreviews.org This article’s doi: Abstract 10.1146/annurev-biochem-060713-035314 Access provided by University of California - San Diego on 06/23/20. For personal use only. Numerous proteins, including cytokines and chemokines, enzymes and Copyright c 2014 by Annual Reviews. enzyme inhibitors, extracellular matrix proteins, and membrane recep- All rights reserved tors, bind heparin. Although they are traditionally classified as heparin- binding proteins, under normal physiological conditions these proteins actually interact with the heparan sulfate chains of one or more mem- brane or extracellular proteoglycans. Thus, they are more appropriately classified as heparan sulfate–binding proteins (HSBPs).
    [Show full text]
  • Glypican (Heparan Sulfate Proteoglycan) Is Palmitoylated, Deglycanated and Reglycanated During Recycling in Skin Fibroblasts
    Glycobiology vol. 7 no. 1 pp. 103-112, 1997 Glypican (heparan sulfate proteoglycan) is palmitoylated, deglycanated and reglycanated during recycling in skin fibroblasts Gudrun Edgren1, Birgitta Havsmark, Mats Jonsson and granules (for reviews, see Kjell6n and Lindahl, 1991; Bernfield Lars-Ake Fransson et al., 1992; David, 1993; Heinegard and Oldberg, 1993). Pro- teoglycans are classified according to the characteristic fea- Department of Cell and Molecular Biology, Faculty of Medicine, Lund University, Lund, Sweden tures or properties of the core protein and can appear in many 'To whom correspondence should be addressed at: Department of Cell and glycoforms giving rise to considerable structural variation and Downloaded from https://academic.oup.com/glycob/article/7/1/103/725516 by guest on 30 September 2021 Molecular Biology 1, POB 94, S-221 00, Lund, Sweden functional diversity. In general, the protein part determines the destination of the proteoglycan and interacts with other mol- Skin fibroblasts treated with brefeldin A produce a recy- ecules at the final location. The glycan part provides the overall cling variant of glypican (a glycosylphosphatidylinositol- bulk properties as well as binding sites for other gly- anchored heparan-sulfate proteoglycan) that is resistant to cosaminoglycans and many types of proteins, including matrix inositol-specific phospholipase C and incorporates sulfate proteins, plasma proteins, enzymes, anti-proteinases, growth and glucosamine into heparan sulfate chains (Fransson, factors, and cytokines. L.-A. et aL, Glycobiology, 5, 407-415, 1995). We have now Cultured human fibroblasts synthesize, deposit, and secrete investigated structural modifications of recycling glypican, 3 a variety of proteoglycans and have been used extensively to such as fatty acylation from [ H]palmitate, and degrada- investigate both their biosynthesis and functional properties tion and assembly of heparan sulfate side chains.
    [Show full text]
  • Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use
    Molecules 2015, 20, 6342-6388; doi:10.3390/molecules20046342 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use Paola Chiodelli, Antonella Bugatti, Chiara Urbinati and Marco Rusnati * Section of Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy; E-Mails: [email protected] (P.C.); [email protected] (A.B.); [email protected] (C.U.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +39-030-371-7315; Fax: +39-030-371-7747. Academic Editor: Els Van Damme Received: 26 February 2015 / Accepted: 1 April 2015 / Published: 10 April 2015 Abstract: Angiogenesis, the process of formation of new blood vessel from pre-existing ones, is involved in various intertwined pathological processes including virus infection, inflammation and oncogenesis, making it a promising target for the development of novel strategies for various interventions. To induce angiogenesis, angiogenic growth factors (AGFs) must interact with pro-angiogenic receptors to induce proliferation, protease production and migration of endothelial cells (ECs). The action of AGFs is counteracted by antiangiogenic modulators whose main mechanism of action is to bind (thus sequestering or masking) AGFs or their receptors. Many sugars, either free or associated to proteins, are involved in these interactions, thus exerting a tight regulation of the neovascularization process. Heparin and heparan sulfate proteoglycans undoubtedly play a pivotal role in this context since they bind to almost all the known AGFs, to several pro-angiogenic receptors and even to angiogenic inhibitors, originating an intricate network of interaction, the so called “angiogenesis glycomic interactome”.
    [Show full text]
  • Binding of Heparin and of the Small Proteoglycan Decorin to the Same
    Binding of Heparin and of the Small Proteoglycan Decorin to the Same Endocytosis Receptor Proteins Leads to Different Metabolic Consequences Heinz Hausser and Hans Kresse Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, D-4400 Münster, Germany Abstract. Decorin, a small interstitial dermatan sul- there was competition for binding to the 51- and 26- fate proteoglycan, is turned over in cultured cells of kD proteins between heparin and decorin. In spite of mesenchymal origin by receptor-mediated endocytosis its high-affinity binding, heparin was poorly cleared followed by intralysosomal degradation. Two en- from the medium of cultured cells and then catabo- dosomal proteins of 51 and 26 kD have been impli- lized in lysosomes. In contrast to decorin, binding of cated in the endocytotic process because of their inter- heparin to the 51- and MAD proteins was insensitive action with decorin core protein. However, heparin to acidic pH, thus presumably preventing its dissocia- and protein-free dermatan sulfate were able to inhibit tion from the receptor in the endosome. Recycling of endocytosis of decorin in a concentration-dependent heparin to the cell surface after internalization could manner. After Western blotting of endosomal proteins, indeed be demonstrated. DCORIN (small dermatan sulfate proteoglycan II) is a tosis (27, 40) . Lysine and arginine residues have been shown member of the family of small interstitial proteo- to be important for the uptake properties (8), although the j/J) glycans (14, 28). It has been found in all tissues so structure of the receptor-binding domain of the core protein far investigated (43) . The mature molecule consists of a core is not yet known.
    [Show full text]
  • Cartilage Proteoglycans
    seminars in CELL & DEVELOPMENTAL BIOLOGY, Vol. 12, 2001: pp. 69–78 doi:10.1006/scdb.2000.0243, available online at http://www.idealibrary.com on Cartilage proteoglycans Cheryl B. Knudson∗ and Warren Knudson The predominant proteoglycan present in cartilage is the tural analysis. The predominate glycosaminoglycan large chondroitin sulfate proteoglycan ‘aggrecan’. Following present in cartilage has long been known to be its secretion, aggrecan self-assembles into a supramolecular chondroitin sulfate. 2 However, extraction of the structure with as many as 50 monomers bound to a filament chondroitin sulfate in a more native form, as a of hyaluronan. Aggrecan serves a direct, primary role pro- proteoglycan, proved to be a daunting task. The viding the osmotic resistance necessary for cartilage to resist revolution in the field came about through the compressive loads. Other proteoglycans expressed during work of Hascall and Sajdera. 3 With the use of the chondrogenesis and in cartilage include the cell surface strong chaotropic agent guanidinium hydrochlo- syndecans and glypican, the small leucine-rich proteoglycans ride, the proteoglycans of cartilage could now be decorin, biglycan, fibromodulin, lumican and epiphycan readily extracted and separated into relatively pure and the basement membrane proteoglycan, perlecan. The monomers through the use of CsCl density gradient emerging functions of these proteoglycans in cartilage will centrifugation. This provided the means to identify enhance our understanding of chondrogenesis and cartilage and characterize the major chondroitin sulfate pro- degeneration. teoglycan of cartilage, later to be termed ‘aggrecan’ following the cloning and sequencing of its core Key words: aggrecan / cartilage / CD44 / chondrocytes / protein. 4 From this start, aggrecan has gone on to hyaluronan serve as the paradigm for much of proteoglycan c 2001 Academic Press research.
    [Show full text]
  • Part II—Chapter 5: the Biological Activity of Chondroitin Sulfate
    98 Part II—Chapter 5: The Biological Activity of Chondroitin Sulfate Glycosaminoglycans ∗ General functions of glycosaminoglycans Proteoglycans are a diverse class of proteins that carry long chains of carbohydrate polymers termed glycosaminoglycans.1, 2 Glycosaminoglycans (GAGs) are chains of repeating disaccharide units that show tremendous structural diversity with complex patterns of deacetylation, sulfation, length, and epimerization.3, 4 The GAG chains are covalently bound to proteins via the hydroxyl group of specific serine residues found in the protein core.5, 6 Proteoglycans are found in the extracellular matrix of all tissues, including cartilage, basement membranes, and connective tissue, as well as on the surface of most cells. The diversity seen among the different proteoglycan families arises from the variety of protein cores available as well as from variations in the length and type of attached GAG chains. Proteoglycans found in the brain are expressed under strict control throughout nervous system development, and they act as regulators of axonal pathfinding, cell migration, and synaptogenesis.1, 7 -- 9 Proteoglycans act as scaffold structures constructed to interact with other proteins through noncovalent binding to their GAG chains. In the brain, a variety of proteoglycan families are involved in binding growth factors, cell adhesion molecules, enzymes, and enzyme inhibitors.1 Both the syndecan and glypican proteoglycan families bind to the neural cell adhesion molecule (NCAM), slit-1 and slit-2, which are involved in the development of midline glia and axon pathways, different members of the fibroblast ∗ Portions of this chapter were taken from C. I. Gama and L. C. Hsieh-Wilson (2005) Curr.
    [Show full text]
  • Glycosaminoglycans and Proteoglycans
    pharmaceuticals Editorial Glycosaminoglycans and Proteoglycans Vitor H. Pomin 1 and Barbara Mulloy 2,* 1 Program of Glycobiology, Institute of Medical Biochemistry Leopoldo de Meis and University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil; [email protected] 2 Glycosciences Laboratory, Department of Medicine, Imperial College London, Burlington Danes Building, Du Cane Road, London W12 0NN, UK * Correspondence: [email protected] Received: 19 February 2018; Accepted: 26 February 2018; Published: 27 February 2018 Abstract: In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end. Keywords: chondroitin sulfate; decorin; dermatan sulfate; glycosaminoglycans; glypican; heparan sulfate; heparin; hyaluronan; keratan sulfate; perlecan; proteoglycans; serglycin; syndecan 1. Introduction This short article is intended to provide a brief introduction to the structures of glycosaminoglycans (GAGs) and proteoglycans (PGs) to set the articles in this special issue of Pharmaceuticals on “Proteoglycans and Glycosaminoglycans” into context. The class of glycosylated proteins known as PGs is represented in the pharmaceutical world chiefly by its carbohydrate constituents. These are polysaccharides known as GAGs, such as heparin (Hp) [1] and chondroitin sulfate (CS) [2]. When attached to their native protein cores these polysaccharides form the glycoconjugates known as PGs.
    [Show full text]
  • Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor
    International Journal of Molecular Sciences Article Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor Marissa L. Maciej-Hulme 1,*,† , Eamon Dubaissi 2, Chun Shao 3, Joseph Zaia 3 , Enrique Amaya 2 , Sabine L. Flitsch 4 and Catherine L. R. Merry 1,*,‡ 1 Materials Science Centre, School of Materials, The University of Manchester, Grosvenor St., Manchester M1 7HS, UK 2 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK; [email protected] (E.D.); [email protected] (E.A.) 3 Center for Biomedical Mass Spectrometry, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA; [email protected] (C.S.); [email protected] (J.Z.) 4 School of Chemistry & Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK; [email protected] * Correspondence: [email protected] (M.L.M.-H.); [email protected] (C.L.R.M.) † Current address: Department of Nephrology, Radboudumc, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. ‡ Current address: Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Citation: Maciej-Hulme, M.L.; Nottingham NG7 2RD, UK. Dubaissi, E.; Shao, C.; Zaia, J.; Amaya, E.; Flitsch, S.L.; Merry, C.L.R. Abstract: The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental pro- Selective Inhibition of Heparan cesses. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors Sulphate and Not Chondroitin can be used to perturb HS function and these compounds provide cheap alternatives to genetic Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor.
    [Show full text]
  • Glycosaminoglycans in Tissue Engineering: a Review
    biomolecules Review Glycosaminoglycans in Tissue Engineering: A Review Harkanwalpreet Sodhi 1 and Alyssa Panitch 1,2,* 1 Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA; [email protected] 2 Department of Surgery, University of California Davis, Sacramento, CA 95817, USA * Correspondence: [email protected] Abstract: Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions. Keywords: glycosaminoglycans; tissue engineering; extracellular matrix; chondroitin sulfate; hyaluronic acid; dermatan sulfate; keratan sulfate; heparan sulfate 1. Introduction Glycosaminoglycans (GAGs) are long, unbranched polysaccharide chains made up primarily of repeating disaccharide units. These disaccharide subunits are composed Citation: Sodhi, H.; Panitch, A. of one hexuronic acid and one amino sugar linked by glycosidic bonds [1] and these Glycosaminoglycans in Tissue variations in disaccharide composition are used to distinguish the major classes of GAGs: Engineering: A Review. Biomolecules Hyaluronic Acid (HA), Chondroitin Sulfate (CS), Dermatan Sulfate (DS), Keratan Sulfate 2021, 11, 29. https://doi.org/10.33 (KS), and Heparan Sulfate (HS).
    [Show full text]
  • Heparan Sulfate Proteoglycans: Structure, Protein Interactions and Cell Signaling
    “main” — 2009/7/27 — 14:11 — page 409 — #1 Anais da Academia Brasileira de Ciências (2009) 81(3): 409-429 (Annals of the Brazilian Academy of Sciences) ISSN 0001-3765 www.scielo.br/aabc Heparan sulfate proteoglycans: structure, protein interactions and cell signaling , JULIANA L. DREYFUSS1, CAIO V. REGATIERI1 2, THAIS R. JARROUGE1, RENAN P. CAVALHEIRO1, LUCIA O. SAMPAIO1 and HELENA B. NADER1 1Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo Rua Três de Maio, 100, 04044-020 São Paulo, SP, Brasil 2Departamento de Oftalmologia, Universidade Federal de São Paulo, Rua Botucatu, 822, 04023-062 São Paulo, SP, Brasil Manuscript received on August 26, 2008; accepted for publication on October 8, 2008; contributed by HELENA B. NADER* ABSTRACT Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton inter- actions leading to gene regulation.
    [Show full text]
  • A Functional Heparan Sulfate Mimetic Implicates Both Heparanase and Heparan Sulfate in Tumor Angiogenesis and Invasion in a Mouse Model of Multistage Cancer
    Oncogene (2005) 24, 4037–4051 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer Johanna A Joyce*,1, Craig Freeman2, Nicole Meyer-Morse1, Christopher R Parish2 and Douglas Hanahan*,1 1Department of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0534, USA; 2Division of Immunology and Genetics, The John Curtin School of Medical Research, The Australian National University, PO Box 334, Canberra, ACT, 2601 Australia Heparan sulfate proteoglycans are integral components of Keywords: heparanase; heparan sulfate-binding pro- the extracellular matrix that surrounds all mammalian teins; invasion; angiogenesis; pancreatic neuroendocrine cells. In addition to providing structural integrity, they act cancer; mouse model as a storage depot for a variety of heparan sulfate (HS)- binding proteins, including growth factors and chemo- kines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, Introduction as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and The structural integrity of cells within normal tissues is protein expression are increased in the neoplastic stages provided in large part by different classes of macro- progressively unfolding in a mouse model of multistage molecules embedded in underlying basement mem- pancreatic islet carcinogenesis. Notably, heparanase is branes (BM) and the extracellular matrix (ECM). delivered to the neoplastic lesions in large part by These include heparan sulfate proteoglycans (HSPGs), infiltrating Gr1 þ /Mac1 þ innate immune cells.
    [Show full text]