Abstract:
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. Visual Overview: An online visual overview is available for this article.
journal_name
Circ Resjournal_title
Circulation researchauthors
Rykaczewska U,Suur BE,Röhl S,Razuvaev A,Lengquist M,Sabater-Lleal M,van der Laan SW,Miller CL,Wirka RC,Kronqvist M,Gonzalez Diez M,Vesterlund M,Gillgren P,Odeberg J,Lindeman JH,Veglia F,Humphries SE,de Faire U,Baldassdoi
10.1161/CIRCRESAHA.119.316063subject
Has Abstractpub_date
2020-02-28 00:00:00pages
571-585issue
5eissn
0009-7330issn
1524-4571journal_volume
126pub_type
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journal_title:Circulation research
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更新日期:2012-02-03 00:00:00
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更新日期:2012-08-03 00:00:00
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