Heparan sulfate proteoglycans (HSPGs) are composed of negatively charged heparan sulfate
(HS) chains linked to a core protein. HS chains have an ancient evolutionary history,
and are highly conserved. Virtually every cell type in metazoan (multicellular animals)
organisms produces HS. The chains are synthesized by a highly ordered sequence of
enzymatic events in the Golgi apparatus and are present on cell surface membranes,
membranes of intracellular organelles, basement membranes, and in the extracellular
matrix. These complex polysaccharides serve as low-affinity receptors to numerous
proteins that contain a heparin-binding domain. Modulation of the HS chains may potentially
affect cell surface interactions with numerous molecules, cells, and microparticles.[1] As HSPGs are important gatekeepers at the cell surface, they are involved in ample
biological processes including hemostasis. In the present issue of Seminars in Thrombosis and Hemostasis, we introduce several fields where a significant role of HSPGs has been established,
making them an important mechanism linking hemostasis, inflammation, angiogenesis,
and cancer. Research in the field of HS chains is lagging behind because of the lack
of advanced laboratory assays. While the protein part in the HSPGs complex (e.g.,
syndecan) can be easily evaluated using an antibody interacting with the protein,
commercially available assays to assess the sugar chains of HS are sparse.
HSPGs in Human Pathologies
HSPGs in Human Pathologies
In the present issue, Vlodavsky at al discuss the effect of the heparanase protein
on the HS chains, and outline how the modification of HS chains acts in processes
such as inflammation, angiogenesis, and tumor growth.[2] Heparanase is the only enzyme in vertebrates known to degrade HS chains, and thus
the only known modulator of HS activity. Heparanase is able to degrade HS chains in
only one specific site, which is the antithrombin-binding pentasaccharide sequence.
In addition, heparanase induces release of the HSPG syndecan from cell surfaces. Intervening
in heparanase activity is a potential way to affect HS chains length and level, and
could be beneficial in diseases in which inflammation or angiogenesis are relevant
as well as in cancer. Next, Nadir discusses the effect of heparanase and HS chains
on the hemostatic system.[3] Heparanase has been shown to directly affect the coagulation system by enhancing
tissue factor activity. In addition, the interaction of antithrombin and tissue factor
pathway inhibitor with HS chains is a key mechanism of thrombosis prevention. Degradation
of HS chains by heparanase at the endothelial cell surface and release of these anticoagulant
proteins, may tip the balance toward a procoagulant milieu. The next contribution
by Hiebert demonstrates that in diabetes, modified HSPGs in the endothelium and extracellular
matrix contribute to nephropathy, cardiovascular disease, and retinopathy present
in diabetes.[4] The interaction between high glucose levels and heparanase upregulation, resulting
in modulation of HS chains in cells, is described and the role of heparanase in enhancing
atherosclerosis and hampering lipid metabolism is discussed. Oshima et al then analyze
the influence of endothelial HSPGs shedding that occurs during sepsis in terms of
endothelial cell function and show that local and systemic vascular dysfunction is
in part mediated by HSPGs.[5] Potential therapeutic strategies to improve vascular function in patients with sepsis
are outlined. Another interesting aspect touched upon in this issue is the involvement
of HSPGs in viral infection as depicted by Koganti et al.[6] Numerous viruses often interact with the HSPGs on endothelial or epithelial cells
at the time of attachment. Thus, the cell surface HSPGs are used as receptors for
viral entry into cells. Identification of the mechanisms underlying cell surface interactions
between viruses and cells via HS may broaden our understanding of other cell–cell
and cell–microparticle interactions. Using competitive inhibitors of HS, such as heparin
molecules, early during infection could lead to a significant decrease in viral infectivity.
HSPGs as Biomarkers and Treatment Targets
HSPGs as Biomarkers and Treatment Targets
Lepedda et al then introduce the diagnostic and prognostic value of circulating HSPGs.[7] The level of HSPG released into the bloodstream is demonstrated to correlate with
disease severity in various pathologies such as cardiovascular disease, cancer, sepsis,
and trauma. Whether the level of HSPG shed into plasma could be used as a prognostic
biomarker in health and disease needs to be further investigated. HSPGs are established
as key regulators and mediators of neural development. Peall et al thus present an
overview on the current knowledge in three-dimensional human neural stem cell models,
discussing their application in exploring HSPGs and the neural extracellular niche.[8] Better understanding of the role of HSPGs in neurologic pathologies could advance
therapeutic approaches. Moreover, these models might be applicable to HS research
on other stem cell types and their extracellular niche. Gerlza et al then provide
insights into the development of new drug compositions and methods targeting HSPGs
and heparanase in cancer and inflammatory diseases.[9] These studies are ongoing and will hopefully pave the way to novel strategies in
cancer and rheumatic treatment.
HSPGs as a Link between Hemostasis, Cancer, and Inflammation
HSPGs as a Link between Hemostasis, Cancer, and Inflammation
[Table 1] summarizes the main knowledge on HSPGs presented in this issue. The involvement
of HSPGs in hemostasis, cancer, angiogenesis, and inflammation may imply that these
molecules, located on the cell surface, could be a vital link in various physiological
and pathological processes. Development of accurate and efficient measurement tools
to evaluate HS chain length, charge, and level would contribute to the elucidation
of the HS role as a porter at membrane surfaces.
Table 1
Heparan sulfate proteoglycans (HSPGs) are involved in numerous physiological and pathological
processes and may be utilized as biomarkers and therapy targets
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HSPGs are present:
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On the cell surface
On the intracellular organelle surface membranes (e.g., nucleus)
In the basement membrane and extracellular matrix
|
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HSPGs are:
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Endothelial anticoagulants
Low affinity receptors to numerous proteins
Effectors of cell–cell interactions, cell–extracellular microvesicles interactions,
and cell–virus interactions
|
|
HSPGs are involved in:
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Hemostasis
Diabetic complications in the kidney, heart, and eye
Sepsis, inflammation
Viral infections
Neurogenesis
|
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Posttranslation, heparan sulfate chains are modulated by a single enzyme named heparanase
Heparanase affects:
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Hemostasis
Inflammation
Angiogenesis
Cancer growth
|
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HSPGs applications:
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Biomarkers: diagnostic and prognostic
Targets to therapy by inhibition of: heparan sulfate chains, HSPGs, heparanase
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