SwePub
Sök i LIBRIS databas

  Extended search

(WFRF:(Suur Bianca E))
 

Search: (WFRF:(Suur Bianca E)) > Therapeutic potenti...

  • Suur, Bianca E.Karolinska Institutet (author)

Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-09-15
  • Frontiers Media SA,2022
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-320477
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-320477URI
  • https://doi.org/10.3389/fphar.2022.988561DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:150837245URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20221026
  • Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from PCSK4, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in plaques vs. control arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between FURIN plaque levels and serum LDL, while PCSK6 was negatively associated with Hb. PCSK5/6/7 were all positively associated with adverse cardiovascular events. Our results show that PCSK6 is abundant in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel 'molecular' 5D framework. Here, we conducted the first integrative study of the proprotein convertase family in this context. Our results using this translational pipeline, revealed primarily PCSK6, followed by PCSK5, PCSK7 and FURIN, as proprotein convertases with the highest novel therapeutic potential.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Chemaly, MelodyKarolinska Institutet (author)
  • Liljeqvist, Moritz LindquistKarolinska Institutet (author)
  • Djordjevic, DjordjeKarolinska Institutet (author)
  • Stenemo, MarkusKarolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. (author)
  • Bergman, OttoKarolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden. (author)
  • Karlof, EvaKarolinska Institutet (author)
  • Lengquist, MarietteKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (author)
  • Odeberg, Jacob,Professor,1963-KTH,Science for Life Laboratory, SciLifeLab,Proteinvetenskap,Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.(Swepub:kth)u1e4yljo (author)
  • Hurt-Camejo, EvaKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;AstraZeneca, Biopharmaceut R&D, Mölndal, Sweden. (author)
  • Eriksson, PerKarolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden. (author)
  • Ketelhuth, Daniel F. J.Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.;Univ Southern Denmark, Dept Cardiovasc & Renal Res, Odense, Denmark. (author)
  • Roy, JoyKarolinska Institutet (author)
  • Hedin, UlfKarolinska Institutet (author)
  • Nyberg, MichaelNovo Nordisk AS, Global Drug Discovery, Malov, Denmark. (author)
  • Matic, LjubicaKarolinska Institutet (author)
  • Karolinska InstitutetKarolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. (creator_code:org_t)

Related titles

  • In:Frontiers in Pharmacology: Frontiers Media SA131663-9812

Internet link

Find in a library

To the university's database

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Close

Copy and save the link in order to return to this view