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PCSK6 Is a Key Prot...
PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
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- Rykaczewska, Urszula (author)
- Karolinska Institutet
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- Suur, Bianca E. (author)
- Karolinska Institutet
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- Rohl, Samuel (author)
- Karolinska Institutet
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- Razuvaev, Anton (author)
- Karolinska Institutet
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- Lengquist, Mariette (author)
- Karolinska Institutet
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- Sabater-Lleal, Maria (author)
- Karolinska Institutet
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- van der Laan, Sander W. (author)
- Univ Utrecht, Univ Med Ctr Utrecht, Cent Diagnost Lab, Pharm & Biomed Genet, Utrecht, Netherlands.
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- Miller, Clint L. (author)
- Univ Virginia, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA USA.;Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
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- Wirka, Robert C. (author)
- Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
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- Kronqvist, Malin (author)
- Karolinska Institutet
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- Diez, Maria Gonzalez (author)
- Karolinska Univ Hosp Solna, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Stockholm, Sweden.
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- Vesterlund, Mattias (author)
- Karolinska Institutet
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- Gillgren, Peter (author)
- Karolinska Institutet
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- Odeberg, Jacob, Professor, 1963- (author)
- Karolinska Institutet,KTH,Science for Life Laboratory, SciLifeLab,Cellulär och klinisk proteomik,Karolinska Univ Hosp Solna, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Stockholm, Sweden.;KTH, Sch Chem Biotechnol & Hlth CBH, Dept Prote, Sci Life Lab, Stockholm, Sweden.
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- Lindeman, Jan H. (author)
- Leiden Univ, Med Ctr, Dept Vasc Surg, Leiden, Netherlands.
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- Veglia, Fabrizio (author)
- IRCCS, Ctr Cardiol Monzino, Milan, Italy.
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- Humphries, Steve E. (author)
- UCL, Inst Cardiovasc Sci, Dept Med, Cardiovasc Genet, Rayne Bldg, London, England. Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.
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- de Faire, Ulf (author)
- Karolinska Institutet
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- Baldassarre, Damiano (author)
- IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy.
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- Tremoli, Elena (author)
- IRCCS, Ctr Cardiol Monzino, Milan, Italy.
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- Lehtio, Janne (author)
- Karolinska Institutet
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- Hansson, Goran K. (author)
- Karolinska Institutet
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- Paulsson-Berne, Gabrielle (author)
- Karolinska Institutet
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- Pasterkamp, Gerard (author)
- Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol, Utrecht, Netherlands.
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- Quertermous, Thomas (author)
- Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
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- Hamsten, Anders (author)
- Karolinska Institutet
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- Eriksson, Per (author)
- Karolinska Institutet
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- Hedin, Ulf (author)
- Karolinska Institutet
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- Matic, Ljubica (author)
- Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp Solna, Stockholm, Sweden.
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Karolinska Institutet Univ Utrecht, Univ Med Ctr Utrecht, Cent Diagnost Lab, Pharm & Biomed Genet, Utrecht, Netherlands (creator_code:org_t)
- LIPPINCOTT WILLIAMS & WILKINS, 2020
- 2020
- English.
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In: Circulation Research. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7330 .- 1524-4571. ; 126:5, s. 571-585
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Rationale: PCSKs (Proprotein convertase subtilisins/kexins) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix remodeling, and mitogens. Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall. Methods and Results: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions versus healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localized to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB (platelet-derived growth factor subunit B) and MMP (matrix metalloprotease) 2/MMP14. Here, PCSK6 was shown to colocalize and cointeract with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6(-/-) versus control mice revealed suppression of contractile SMC markers, extracellular matrix remodeling enzymes, and cytokines/receptors. Pcsk6(-/-) mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro leads to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB (platelet-derived growth factor BB)-induced cell proliferation and particularly migration. Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Keyword
- atherosclerosis
- carotid artery injuries
- endarterectomy
- extracellular matrix
- vascular remodeling
Publication and Content Type
- ref (subject category)
- art (subject category)
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Rykaczewska, Urs ...
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Suur, Bianca E.
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Rohl, Samuel
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Razuvaev, Anton
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Lengquist, Marie ...
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Sabater-Lleal, M ...
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show more...
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van der Laan, Sa ...
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Miller, Clint L.
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Wirka, Robert C.
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Kronqvist, Malin
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Diez, Maria Gonz ...
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Vesterlund, Matt ...
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Gillgren, Peter
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Odeberg, Jacob, ...
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Lindeman, Jan H.
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Veglia, Fabrizio
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Humphries, Steve ...
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de Faire, Ulf
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Baldassarre, Dam ...
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Tremoli, Elena
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Lehtio, Janne
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Hansson, Goran K ...
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Paulsson-Berne, ...
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Pasterkamp, Gera ...
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Quertermous, Tho ...
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Hamsten, Anders
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Eriksson, Per
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Hedin, Ulf
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Matic, Ljubica
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Circulation Rese ...
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Royal Institute of Technology
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Karolinska Institutet