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

Abstract

Integrins are heterodimeric alpha/beta 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 alpha(v) 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 alpha(v)beta3 cell-surface expression. Inhibition of furin/PC5 with the specific pharmacological furin-like PC-inhibitor dec-CMK inhibited alpha(v) endoproteolytic activation but did not abolish alpha(v)beta3 cell-surface expression. This indicates that furin/PC5 is required for alpha(v) endoproteolytic activation but not for alpha(v) 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 alpha(v) endoproteolytic activation.

• Authors: Philipp Stawowy, Heike Kallisch, Núbia Borges Pereira Stawowy, Dietger Stibenz, John P Veinot, Michael Gräfe, Nabil G Seidah, Michel Chrétien, Eckart Fleck, Kristof Graf
• Journal: Virchows Archiv : an international journal of pathology (Virchows Arch) Vol. 446 Issue 4 Pg. 351-9 (Apr 2005) ISSN: 0945-6317 [Print] Germany
• PMID: 15756593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Enzyme Inhibitors
• Integrin alphaVbeta3
• Membrane Proteins
• Proprotein Convertase 5
• FURIN protein, human
• Furin

Topics

• Arteriosclerosis (enzymology, pathology)
• Biomarkers (metabolism)
• Cell Line, Tumor
• Endothelium, Vascular (enzymology, pathology)
• Enzyme Inhibitors (pharmacology)
• Femoral Artery (enzymology, pathology)
• Flow Cytometry
• Furin (antagonists & inhibitors, metabolism)
• Humans
• Immunohistochemistry (methods)
• Integrin alphaVbeta3 (metabolism)
• Macrophages (enzymology, pathology)
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Muscle, Smooth, Vascular (enzymology, pathology)
• Proprotein Convertase 5 (antagonists & inhibitors, metabolism)