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Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis

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Abstract

Integrins are heterodimeric α/β receptors that link the cytoskeleton with the extracellular matrix, thereby regulating several cell functions important in atherosclerosis. In vitro, the subtilisin/kexin-like proprotein convertases (PCs), namely PC5 and furin, have been shown to be responsible for the endoproteolytic activation of the αv integrin subunit. Based on their cleavage activity, these PCs are potential targets in atherosclerosis. In the present study, we investigated the localization of furin and PC5 in different stages of human atherosclerosis. Immunohistochemical analysis of furin and PC5 revealed their presence in vascular smooth-muscle cells and endothelial cells in atherosclerotic and non-atherosclerotic lesions. However, in the more advanced lesions, furin and PC5 staining was significantly expressed in macrophages/foam cells. In vitro, THP-1 derived macrophages contained furin and PC5, and maturation of monocytes to macrophages was accompanied by enhanced αvβ3 cell-surface expression. Inhibition of furin/PC5 with the specific pharmacological furin-like PC-inhibitor dec-CMK inhibited αv endoproteolytic activation but did not abolish αvβ3 cell-surface expression. This indicates that furin/PC5 is required for αv endoproteolytic activation but not for αv routing and sorting to the cell surface. In conclusion, our study demonstrates that furin and PC5 are significantly expressed in mononuclear cells in advanced human atherosclerotic lesions, where they regulate αv endoproteolytic activation.

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Acknowledgements

This work was supported by grants from the Bundesministerium für Bildung und Forschung (BMBF) (CAN02/005) to PS and EF and Canadian Institutes of Health Research (CIHR) (MGP-44363) to NGS. JPV and MC were supported from the Heart and Stroke Foundation of Ontario (NA4337 and T4891) and the Canadian Stroke Network.

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Authors and Affiliations

  1. Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Philipp Stawowy, Heike Kallisch, Núbia Borges Pereira Stawowy, Dietger Stibenz, Michael Gräfe, Eckart Fleck & Kristof Graf

  2. Diseases of Aging and Regional Protein Chemistry Centers, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada

    John P. Veinot & Michel Chrétien

  3. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute, Montréal, Quebec, Canada

    Nabil G. Seidah

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  1. Philipp Stawowy
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Correspondence to Philipp Stawowy.

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Stawowy, P., Kallisch, H., Borges Pereira Stawowy, N. et al. Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis. Virchows Arch 446, 351–359 (2005). https://doi.org/10.1007/s00428-004-1198-7

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  • DOI: https://doi.org/10.1007/s00428-004-1198-7

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