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Molecular Structure of Heparan Sulfate from Spalax: IMPLICATIONS OF HEPARANASE AND HYPOXIA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 6, 3814-3822 p.Article in journal (Refereed) Published
Abstract [en]

Spalax, a subterranean blind mole rat, is well adapted to live in an extreme hypoxic environment through up-regulated expression of growth factors and enzymes for ensuring sufficient oxygen supply. One of the overexpressed enzymes is heparanase, an endoglucuronidase that selectively cleaves heparan sulfate (HS) and is implicated in angiogenesis. To assess the implications of the heparanase in Spalax, we have characterized the structure of HS isolated from various organs of the animal. The oligosaccharides obtained after deaminative cleavage of HS samples from the tissues show an overall higher sulfation degree, distinct from that of murine tissues. Of particular significance was the appearance of a trisaccharide moiety in the tissues examined, apart of the even numbered oligosaccharide fractions typically found in HS from human and mouse tissues. The formation of this odd-numbered saccharide is a consequence of heparanase action, in agreement with the notion of high expression of the enzyme in this species. Analysis of HS extracted from human embryonic kidney cells (HEK293) after exposure to hypoxic condition revealed a structural change in the distribution of oligosaccharides similar to HS derived from Spalax organs. The alterations are likely due to up-regulated activity of heparanase, as real-time RT-PCR showed a 2-fold increase in heparanase mRNA expression in the hypoxia treated cells. HEK293 cells stably overexpressing Spalax heparanase produced HS sharing similarity with that from the Spalax organs, and exhibited enhanced MAPK activity in comparison with HEK293 cells, indicating a regulation role of the heparanase in the activity of growth factors.

Place, publisher, year, edition, pages
2009. Vol. 284, no 6, 3814-3822 p.
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-98938DOI: 10.1074/jbc.M802196200ISI: 000262872500050PubMedID: 19068480OAI: oai:DiVA.org:uu-98938DiVA: diva2:201678
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Roles of Heparan Sulfate in Amyloid-β Pathology and Hypoxia
Open this publication in new window or tab >>Roles of Heparan Sulfate in Amyloid-β Pathology and Hypoxia
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) is a highly sulfated polysaccharide expressed on the cell surface and in the extracellular matrix, interacting with a large number of proteins. HS is implicated in human diseases, including different types of cancer and amyloid diseases such as Alzheimer's disease (AD). The aims of this thesis were to gain deeper insights into AD and cancer progression by elucidating the roles of HS in amyloid-β (Aβ) pathology and hypoxia.

The toxic Aβ-peptide is a key molecule in AD due to its ability to aggregate and form amyloid plaques in the brains of diseased patients. It has been reported that HS accumulates with Aβ in these amyloid plaques. We have found that HS is differentially accumulated with Aβ species within the amyloid plaques in the brains of AD patients. We also identified that the HS in the plaques originated from glial cells. Further, we investigated the role of HS in Aβ toxicity using cell models that either lack HS or express abnormal HS. The results show that cell surface HS mediates Aβ internalization and cytotoxicity.

Upregulation of heparanase, an endo-glucuronidase that specifically cleaves HS chains, in human cancers increases the potential of tumor cells to metastasize. Spalax, an animal model for hypoxic tolerance, expresses high levels of heparanase. Analysis of HS from different Spalax organs revealed a high sulfation degree and an atypical domain structure, likely modulated by high heparanase expression in the organs. Cells cultured under hypoxic conditions showed a similar HS domain structure and had an increase in heparanase mRNA. We propose that hypoxia-induced heparanase expression is relevant for tumor progression, a process often associated with oxygen deficiency.

Altogether, the findings in this thesis are important for future development of therapeutics aiming at interfering with HS functions in AD and cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 55 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 628
Heparan sulfate, Alzheimer's disease, Aβ, Proteoglycan, Heparanase, Amyloid, Hypoxia, Cancer, Spalax
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
urn:nbn:se:uu:diva-133688 (URN)978-91-554-7963-3 (ISBN)
Public defence
2011-01-22, C10:305, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2010-12-16 Created: 2010-11-15 Last updated: 2011-01-13

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