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Therapeutic potenti...
Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease
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- Suur, Bianca E. (author)
- Karolinska Institutet
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- Chemaly, Melody (author)
- Karolinska Institutet
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- Liljeqvist, Moritz Lindquist (author)
- Karolinska Institutet
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- Djordjevic, Djordje (author)
- Karolinska Institutet
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- Stenemo, Markus (author)
- Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
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- Bergman, Otto (author)
- Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.
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- Karlof, Eva (author)
- Karolinska Institutet
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- Lengquist, Mariette (author)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Odeberg, Jacob, Professor, 1963- (author)
- KTH,Science for Life Laboratory, SciLifeLab,Proteinvetenskap,Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.
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- Hurt-Camejo, Eva (author)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;AstraZeneca, Biopharmaceut R&D, Mölndal, Sweden.
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- Eriksson, Per (author)
- Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.
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- Ketelhuth, Daniel F. J. (author)
- Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden.;Univ Southern Denmark, Dept Cardiovasc & Renal Res, Odense, Denmark.
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- Roy, Joy (author)
- Karolinska Institutet
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- Hedin, Ulf (author)
- Karolinska Institutet
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- Nyberg, Michael (author)
- Novo Nordisk AS, Global Drug Discovery, Malov, Denmark.
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- Matic, Ljubica (author)
- Karolinska Institutet
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Karolinska Institutet Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden (creator_code:org_t)
- 2022-09-15
- 2022
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
- Related links:
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https://doi.org/10.3...
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Abstract
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- 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
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- PCSK
- vascular disease
- carotid plaque
- aortic aneurysm
- therapeutic targeting
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Suur, Bianca E.
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Chemaly, Melody
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Liljeqvist, Mori ...
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Djordjevic, Djor ...
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Stenemo, Markus
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Bergman, Otto
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show more...
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Karlof, Eva
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Lengquist, Marie ...
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Odeberg, Jacob, ...
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Hurt-Camejo, Eva
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Eriksson, Per
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Ketelhuth, Danie ...
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Roy, Joy
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Hedin, Ulf
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Nyberg, Michael
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Matic, Ljubica
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Microbiology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Frontiers in Pha ...
- By the university
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Royal Institute of Technology
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Karolinska Institutet