Title: Proprotein convertases in human atherosclerotic plaques: The overexpression of FURIN and its substrate cytokines BAFF and APRIL
Authors: Turpeinen, Hannu ×
Raitoharju, Emma
Oksanen, Anna
Oksala, Niku
Levula, Mari
Lyytikäinen, Leo-Pekka
Järvinen, Otso
Creemers, John
Kähönen, Mika
Laaksonen, Reijo
Pelto-Huikko, Markku
Lehtimäki, Terho
Pesu, Marko #
Issue Date: Aug-2011
Publisher: Elsevier
Series Title: Atherosclerosis vol:219 issue:2 pages:799-806
Abstract: BACKGROUND: Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave proproteins into mature end products. Previously, MBTPS1 and PCSK9 have been shown to regulate cholesterol metabolism and LDL receptor recycling, whereas FURIN and PCSK5 have been suggested to inactivate lipases and regulate inflammation in atherosclerosis. Here, we systematically analyzed the expression of PCSKs and their targets in advanced atherosclerotic plaques. METHODS AND RESULTS: Microarray and quantitative real-time PCR experiments showed that FURIN (42.86 median fold, p=2.1e-8), but no other PCSK, is universally overexpressed in the plaques of different vascular regions. The mRNA expression screen of PCSK target proteins in plaques identified many known factors, but it also identified the significant upregulation of the previously overlooked furin-processed B cell activating cytokines APRIL (TNFSF13, 2.52 median fold, p=3.0e-5) and BAFF (TNFSF13B, 2.97 median fold, p=7.6e-6). The dysregulation of FURIN did not associate with its htSNPs or the previously reported regulatory SNP (-229, rs4932178) in the promoter. Immunohistochemistry experiments showed the upregulation of FURIN in the plaque lymphocytes and macrophages where it was co-expressed with BAFF/TNFSF13B and APRIL/TNFSF13. CONCLUSIONS: Our data unequivocally show that FURIN is the primary PCSK that is dysregulated in the immune cells of advanced human atherosclerotic plaques, which implies a role for this enzyme in plaque pathology. Therefore, drugs that inhibit FURIN in arteries may modulate the course of this disease.
ISSN: 0021-9150
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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