title: Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL.
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.
  
  
  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.
authors: Immunoregulation, Institute of Biomedical Technology, University of Tampere, Finland.
authors: Hannu
authors: H
authors: Turpeinen
authors: Emma
authors: E
authors: Raitoharju
authors: Anna
authors: A
authors: Oksanen
authors: Niku
authors: N
authors: Oksala
authors: Mari
authors: M
authors: Levula
authors: Leo-Pekka
authors: LP
authors: Lyytikäinen
authors: Otso
authors: O
authors: Järvinen
authors: John W M
authors: JW
authors: Creemers
authors: Mika
authors: M
authors: Kähönen
authors: Reijo
authors: R
authors: Laaksonen
authors: Markku
authors: M
authors: Pelto-Huikko
authors: Terho
authors: T
authors: Lehtimäki
authors: Marko
authors: M
authors: Pesu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D053264:B-Cell Activating Factor / Q000032:analysis* / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005387:Finland; D045683:Furin / Q000032:analysis* / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000032:analysis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D053264:B-Cell Activating Factor; D012333:RNA, Messenger; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C468731:FURIN protein, human; D045683:Furin