• Login
    JavaScript is disabled for your browser. Some features of this site may not work without it.
    A functional study of ADAMTS7 gene variants. 
    •   QMRO Home
    • Queen Mary University of London Theses
    • Theses
    • A functional study of ADAMTS7 gene variants.
    •   QMRO Home
    • Queen Mary University of London Theses
    • Theses
    • A functional study of ADAMTS7 gene variants.
    ‌
    ‌

    Browse

    All of QMROCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects
    ‌
    ‌

    Administrators only

    Login
    ‌
    ‌

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    A functional study of ADAMTS7 gene variants.

    View/Open
    Pu, Xiangyuan 290514.pdf (9.570Mb)
    Publisher
    Queen Mary University of London
    Metadata
    Show full item record
    Abstract
    Background: Recent studies have revealed an association between genetic variants at the ADAMTS7 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7) locus and susceptibility to coronary artery disease (CAD). ADAMTS-7 has been reported to facilitate vascular smooth muscle cell (VSMC) migration and promote neointima formation. We sought to study the functional mechanisms underlying this relationship and to further investigate the role of ADAMTS-7 in atherosclerosis. Methods and Results: In vitro assays showed that the CAD-associated non-synonymous single nucleotide polymorphism rs3825807, which results in a serine to proline (Ser-to- Pro) substitution at residue 214 in the ADAMTS-7 pro-domain, affected ADAMTS-7 prodomain cleavage. Immunohistochemical analyses showed that ADAMTS-7 localised to vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) in human coronary and carotid atherosclerotic plaques. Cell migration assays demonstrated that VSMCs and ECs from individuals who were homozygous for the adenine (A) allele (encoding the Ser214 isoform) had increased migratory ability compared with cells from individuals who were homozygous for the G allele (encoding the Pro214 isoform). Western blot analyses revealed that media conditioned by VSMCs of the A/A genotype contained more cleaved ADAMTS-7 pro-domain and more of the cleaved form of thrombospondin-5 (TSP-5, an ADAMTS-7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration). In in vitro angiogenesis assays, ECs of the A/A genotype exhibited increased capillary-like network formation. ADAMTS-7 over-expression in ECs by transfection of an ADAMTS7-214Ser expressing plasmid significantly accelerated EC migration and in vitro angiogenesis, whereas ADAMTS-7 knockdown by shRNA had opposite effects. Preliminary proteomics analyses of conditioned media of ECs overexpressing ADAMTS-7 and ECs with ADAMTS-7 knockdown indicated that ADAMTS- 7 can cleave thrombospondin-1 (TSP-1), a well-recognised angiogenesis inhibitor. Conclusion: The results of this study indicate that rs3825807 has a functional effect on ADAMTS-7 maturation, TSP-5 cleavage, VSMC and EC migration, and angiogenesis. As VSMC migration and angiogenesis play important roles in atherosclerosis, these results provide a mechanistic explanation for the association between rs3825807 and CAD.
    Authors
    Pu, Xiangyuan
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/9082
    Collections
    • Theses [3366]
    Copyright statements
    The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author
    Twitter iconFollow QMUL on Twitter
    Twitter iconFollow QM Research
    Online on twitter
    Facebook iconLike us on Facebook
    • Site Map
    • Privacy and cookies
    • Disclaimer
    • Accessibility
    • Contacts
    • Intranet
    • Current students

    Modern Slavery Statement

    Queen Mary University of London
    Mile End Road
    London E1 4NS
    Tel: +44 (0)20 7882 5555

    © Queen Mary University of London.