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  • 1
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    Online Resource
    Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN , and SYNM
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Abstract: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Approach and Results— Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7 , and PLN expression positively correlated to typical SMC markers in plaques (Pearson r 〉 0.6, P 〈 0.0001) and in rat intimal hyperplasia ( r 〉 0.8, P 〈 0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN , and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. Conclusions— We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.116.307893
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    Abstract 173: Proprotein Convertase Subtilisin/Kexin Type 6 is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Proprotein convertases (PCSKs) process matrix metalloproteases (MMPs) and cytokines. Apart from PCSK9, the role of these enzymes in vascular disease is largely unknown. Previously, we demonstrated upregulation of PCSK6 in carotid atherosclerosis, primarily localized to smooth muscle cells (SMCs) and positively correlated to inflammation, extracellular matrix remodeling and cytokines. Here, we extended these findings to determine the role of PCSK6 in vascular development and disease. Increased expression of PCSK6 in vascular disease was validated by microarrays from two non-overlapping cohorts of carotid plaques vs. non-atherosclerotic arteries (n=50 patients and n=32 patients, p 〈 0.0001), as well as abdominal (AAA, n=14, p 〈 0.0001) and thoracic aortic aneurysms (TAA, n=244, p=0.012). By eQTL, variants in the PCSK6 gene were found to influence it’s expression in both plaques and aneurysms. Among these, rs6598465 also showed association with maximum progression of carotid intima-media thickness in high-risk coronary artery disease subjects (n=3388, p=0.037). By IHC, PCSK6 localized mainly to SMCs in the fibrous cap and neovessels in atherosclerotic, AAA and TAA tissues. In mouse-, rat-, and human intimal hyperplasia, PCSK6 was expressed in proliferating SMCs. By microarrays, after rat carotid balloon injury there was an early downregulation of PCSK6 followed by an upregulation in later phases during SMC activation, as well as positive correlation to PDGFB and IGF1 (Spearman r 〉 0.7, p 〈 0.0001) and to MMP2 and MMP14 (r 〉 0.5, p 〈 0.0001). In zebrafish embryos, PCSK6 localized to heart and vasculature and its ablation caused defective peripheral vascular patterning with cerebral and myocardial hemorrhage. PCSK6 -/- mice did not present an obvious vascular phenotype but showed reduced intimal hyperplasia compared to wild-type mice after carotid artery ligation (p=0.015). In vitro, PCSK6 overexpression markedly increased SMC migration upon PDGFBB stimulation (p 〈 0.0001). The present study establishes PCSK6 as a key modulator of SMC function in vascular disease and demonstrates a functional link between PCSK6 expression and SMC migration in vascular remodeling.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.173
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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  • 3
    Online Resource
    Online Resource
    Abstract 467: PCSK6 Is Upregulated in Vascular Diseases Characterized by Inflammation and Smooth Muscle Cell Proliferation
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Recently we demonstrated upregulation of the proprotein convertase PCSK6 in a large cohort of human carotid atherosclerotic plaques (n=127) compared to normal arteries and in symptomatic vs. asymptomatic lesions. PCSK6 was localized to smooth muscle cells (SMCs) in the fibrous cap and showed a positive correlation to markers of inflammation, extracellular matrix remodeling and cytokines. Here, we aimed at elucidating the role of this protease in vascular disease by examining its expression in different human pathologies and in animal models. Increased expression of PCSK6 in vascular diseases was validated in public microarray datasets and other available human cohorts. PCSK6 was upregulated in carotid atherosclerotic plaques vs. controls (n=32 patients, p 〈 0.0001), as well as in abdominal aortic aneurysm (AAA) vs. normal tissue (n=14, p 〈 0.0001) and in thoracic aortic aneurysm (TAA) tissue from bicuspid vs. tricuspid patients (n=244, p=0.012). By eQTL analyses, several SNPs in the PCSK6 genomic region were shown to influence its expression in carotid plaques and TAA tissue. Among these, rs6598465 showed a mild association to progression of maximum intima-media thickness in the left and right arteries in a separate cohort of high-risk coronary artery disease subjects (n=3400, p=0.037). By immunohistochemistry, PCSK6 localized mainly to SMCs in carotid plaques, AAA and TAA tissue, but was also found to be expressed by CD68 and CD163+ macrophages. Investigation of mouse, rat and human artery tissues with pronounced intimal hyperplasia revealed strong expression of PCSK6 in proliferating SMCs. In rat carotid artery balloon injury, PCSK6 was downregulated in the early phases after injury mostly defined by inflammatory response, while upregulated in later phases with prominent SMC activation, and consistently localized in SMCs. Expression of PCSK6 in this model was strongly positively correlated solely to PDGFB and IGF1 (p 〈 0.0001), cytokines known to induce SMC proliferation. We established a functional link between elevated expression of PCSK6 and vascular diseases characterized by inflammation and SMC proliferation. Further investigations in vitro are necessary to provide mechanistic insight into the role of this protease in vascular disease.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.467
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Research Vol. 126, No. 5 ( 2020-02-28), p. 571-585
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 126, No. 5 ( 2020-02-28), p. 571-585
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.119.316063
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467838-X
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  • 5
    Online Resource
    Online Resource
    Abstract 150: Identification of SYNPO2, SYNM, LMOD1, PDLIM7 and PLN as Novel Markers of Smooth Muscle Cells in Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Smooth muscle cell (SMC) activation is a hallmark of vascular remodeling associated with downregulation of SMC specific genes and altered cell function. Our aim was to identify a novel set of genes silenced following SMC activation in vascular disease. We compared microarrays from carotid plaques (n=177) vs. undiseased arteries and symptomatic vs. asymptomatic patients and found that ‘muscle contraction’, ‘muscle differentiation’ and ‘cytoskeleton based migration’ were the most significantly downregulated pathways (p=6.06e-23; 5.22e-11; 4.62e-11 respectively). Genes clustered in these categories were known SMC markers together with a novel set of genes functionally coupled to actin cytoskeleton: SYNPO2, SYNM, LMOD1, PDLIM7 and PLN. Transcription factors regulating the expression of these genes showed enrichment of SRF, MYOD1 and MYOGENIN, known to control muscle differentiation. Downregulation of these genes was validated in independent microarrays from carotid (n=21) and coronary plaques (n=38). Their expression was positively correlated to typical SMC markers both in human plaques (Pearson r 〉 0.8, p 〈 0.0001) and rat carotid intimal hyperplasia (r 〉 0.9, p 〈 0.0001). In microarrays from rat carotid balloon injury, these genes were downregulated in the early phases of tissue remodeling but gradually reappeared in the mature intima. By immunohistochemistry, the proteins localized to SMCs in normal human vessels, but were mostly absent in plaques and restenosis tissues. In vitro, SYNPO2 and PDLIM7 localized to actin filaments, SYNM to cortical cytoskeleton, PLN to nucleus while LMOD1 was rapidly lost in cultured human and primary rat SMCs. Polymorphisms in some of these genes associated with carotid intima-media thickness in high-risk coronary artery disease subjects (n=3400). By eQTL analyses, rs11746443 influenced PDLIM7 expression in plaques. Interestingly, this polymorphism constitutes the binding site for HEY1 transcription factor implicated in vascular development. We identified a panel of novel SMC proteins, which are lost in vascular disease and reflect the altered phenotype of SMCs in vascular remodeling. Our results indicate that these could be early and sensitive markers of the SMCs dedifferentiation in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.150
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 6
    Online Resource
    Online Resource
    Abstract 367: Pcsk6 Is a Key Protease Modulating Smooth Muscle Cell Activation in Vascular Remodeling and Plaque Vulnerability
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Proprotein convertases (PCSKs) are conserved among species and involved in processing of MMPs and growth factors, but poorly characterised in atherosclerosis. Previously we demonstrated upregulation of PCSK6 in a large cohort of plaques from symptomatic vs. asymptomatic patients. This protease localized to smooth muscle cells (SMCs) and showed a positive correlation to markers of inflammation, extracellular matrix remodeling and cytokines in plaques. Here we aimed at elucidating its role in vascular development and disease. In zebrafish embryos PCSK6 localized to heart and vasculature and its ablation caused defective peripheral vascular patterning with cerebral and myocardial hemorrhage. Increased expression of PCSK6 in vascular pathologies was validated by microarrays from carotid plaques vs. undiseased arteries (n=32 patients, p 〈 0.0001), abdominal (AAA, n=14, p 〈 0.0001) and thoracic aortic aneurysms (TAA, n=244, p=0.012). By immunohistochemistry, PCSK6 localized mainly to SMCs in the fibrous cap and neo-vessels in plaques, AAA and TAA tissues. Investigation of mouse carotid ligation, rat artery balloon injury and human restenosis tissues with pronounced intimal hyperplasia confirmed induction of PCSK6 in proliferating SMCs. By microarrays following progression of rat carotid injury, PCSK6 was downregulated in early phases defined by inflammatory pathways, while upregulated in later phases with SMCs activation and localized in SMCs. Expression of PCSK6 in this model was positively correlated to PDGFB and IGF1 (Spearman r 〉 0.7, p 〈 0.0001). PCSK6 overexpression in SMCs in vitro increased their migration in a wound-healing assay, especially upon PDGFBB stimulation. By eQTL analyses several polymorphisms in the PCSK6 gene were found to influence its expression in plaques and aneurysm tissue. Among these, rs6598465 showed association with maximum progression of arterial intima-media thickness in high-risk coronary artery disease subjects (n=3400, p=0.037). We identified a functional link between elevated expression of PCSK6 and vascular remodeling characterized by SMC activation. The present study establishes PCSK6 as one of the key modulators of pathological processes in relation to plaque vulnerability.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.367
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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