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  • 1
    Online Resource
    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
    detail.hit.zdb_id: 1494427-3
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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
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    Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
    Elsevier BV ; 2020
    In:  JVS-Vascular Science Vol. 1 ( 2020), p. 13-27
    Details
    In: JVS-Vascular Science, Elsevier BV, Vol. 1 ( 2020), p. 13-27
    Type of Medium: Online Resource
    ISSN: 2666-3503
    URL: Article
    DOI: 10.1016/j.jvssci.2020.01.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 3061185-4
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  • 4
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    Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. 5 ( 2022-05), p. 659-676
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 5 ( 2022-05), p. 659-676
    Abstract: Understanding the processes behind carotid plaque instability is necessary to develop methods for identification of patients and lesions with stroke risk. Here, we investigated molecular signatures in human plaques stratified by echogenicity as assessed by duplex ultrasound. Methods: Lesion echogenicity was correlated to microarray gene expression profiles from carotid endarterectomies (n=96). The findings were extended into studies of human and mouse atherosclerotic lesions in situ, followed by functional investigations in vitro in human carotid smooth muscle cells (SMCs). Results: Pathway analyses highlighted muscle differentiation, iron homeostasis, calcification, matrix organization, cell survival balance, and BCLAF1 (BCL2 [B-cell lymphoma 2]-associated transcription factor 1) as the most significant signatures. BCLAF1 was downregulated in echolucent plaques, positively correlated to proliferation and negatively to apoptosis. By immunohistochemistry, BCLAF1 was found in normal medial SMCs. It was repressed early during atherogenesis but reappeared in CD68+ cells in advanced plaques and interacted with BCL2 by proximity ligation assay. In cultured SMCs, BCLAF1 was induced by differentiation factors and mitogens and suppressed by macrophage-conditioned medium. BCLAF1 silencing led to downregulation of BCL2 and SMC markers, reduced proliferation, and increased apoptosis. Transdifferentiation of SMCs by oxLDL (oxidized low-denisty lipoprotein) was accompanied by upregulation of BCLAF1, CD36, and CD68, while oxLDL exposure with BCLAF1 silencing preserved MYH (myosin heavy chain) 11 expression and prevented transdifferentiation. BCLAF1 was associated with expression of cell differentiation, contractility, viability, and inflammatory genes, as well as the scavenger receptors CD36 and CD68 . BCLAF1 expression in CD68+/BCL2+ cells of SMC origin was verified in plaques from MYH11 lineage-tracing atherosclerotic mice. Moreover, BCLAF1 downregulation associated with vulnerability parameters and cardiovascular risk in patients with carotid atherosclerosis. Conclusions: Plaque echogenicity correlated with enrichment of distinct molecular pathways and identified BCLAF1 , previously not described in atherosclerosis, as the most significant gene. Functionally, BCLAF1 seems necessary for survival and transdifferentiation of SMCs into a macrophage-like phenotype. The role of BCLAF1 in plaque vulnerability should be further evaluated.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.121.317018
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1494427-3
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  • 5
    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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  • 6
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    Online Resource
    Data_Sheet_2.xlsx
    Frontiers Media SA ; 2021
    In:  Frontiers in Cardiovascular Medicine Vol. 8 ( 2021-4-20)
    Details
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 8 ( 2021-4-20)
    Abstract: Objectives and Aims: Vascular smooth muscle cells (VSMCs) are key constituents of both normal arteries and atherosclerotic plaques. They have an ability to adapt to changes in the local environment by undergoing phenotypic modulation. An improved understanding of the mechanisms that regulate VSMC phenotypic changes may provide insights that suggest new therapeutic targets in treatment of cardiovascular disease (CVD). The amino-acid glutamate has been associated with CVD risk and VSMCs metabolism in experimental models, and glutamate receptors regulate VSMC biology and promote pulmonary vascular remodeling. However, glutamate-signaling in human atherosclerosis has not been explored. Methods and Results: We identified glutamate receptors and glutamate metabolism-related enzymes in VSMCs from human atherosclerotic lesions, as determined by single cell RNA sequencing and microarray analysis. Expression of the receptor subunits glutamate receptor, ionotropic, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type subunit 1 (GRIA1) and 2 (GRIA2) was restricted to cells of mesenchymal origin, primarily VSMCs, as confirmed by immunostaining. In a rat model of arterial injury and repair, changes of GRIA1 and GRIA2 mRNA level were most pronounced at time points associated with VSMC proliferation, migration, and phenotypic modulation. In vitro , human carotid artery SMCs expressed GRIA1, and selective AMPA-type receptor blocking inhibited expression of typical contractile markers and promoted pathways associated with VSMC phenotypic modulation. In our biobank of human carotid endarterectomies, low expression of AMPA-type receptor subunits was associated with higher content of inflammatory cells and a higher frequency of adverse clinical events such as stroke. Conclusion: AMPA-type glutamate receptors are expressed in VSMCs and are associated with phenotypic modulation. Patients suffering from adverse clinical events showed significantly lower mRNA level of GRIA1 and GRIA2 in their atherosclerotic lesions compared to asymptomatic patients. These results warrant further mapping of neurotransmitter signaling in the pathogenesis of human atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fcvm.2021.655869
    DOI: 10.3389/fcvm.2021.655869.s001
    DOI: 10.3389/fcvm.2021.655869.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2781496-8
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  • 7
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    Online Resource
    Abstract 627: Combined Plaque Evaluation by Ultrasound and Microarrays Reveals Bclaf1 as a Novel Regulator of Smooth Muscle Cell Transdifferentiation in Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Objective: Understanding molecular processes behind carotid plaque instability is necessary to develop methods that can identify patients and lesions at risk of stroke. Here, we investigated molecular signatures in human plaques stratified by echogenicity as assessed by duplex ultrasound (US). Results: Plaque echogenicity measured by US was correlated to microarray profiles from lesions retrieved at surgery (n=96). Pathway analyses highlighted enrichment of cell apoptosis and proliferation, and BCLAF1 (BCL2 associated factor 1) as the most significantly dysregulated gene (adjusted p 〈 0.0001). BCLAF1 was strongly downregulated in plaques vs. control tissues, positively correlated to markers of cell proliferation and negatively to apoptosis, at both transcriptomic and proteomic level. Immunohistochemistry showed that BCLAF1 was localized in smooth muscle cells (SMCs) nuclei and repressed early during atherogenesis, but reappeared in CD68+ cells in advanced plaques. Proximity ligation assay demonstrated interaction of BCLAF1 with previously reported interaction partners THRAP3 and BCL2, in normal arteries and plaques. In vitro , stimulation of SMCs with pro-survival factors EGF, bFGF, PDGFB resulted in induction of BCLAF1, while it was suppressed by macrophage-conditioned medium. Moreover, BCLAF1 silencing in SMCs led to downregulation of BCL2 and SMC markers, and a decrease in proliferation and adhesion (p 〈 0.0001). Transdifferentiation of SMCs using oxLDL, confirmed by CD68 upregulation and MYH11 repression, was accompanied by upregulation of BCLAF1. However, a combination of oxLDL exposure and BCLAF1 silencing, resulted in preserved expression of MYH11 and prevented transdifferentiation. Finally, BCLAF1 expression in CD68+/BCL2+ cells of SMC origin, was verified in plaques from MYH11-lineage tracing atherosclerotic mice. Conclusions: Carotid plaque echogenicity correlated with enrichment of molecular pathways associated with cell survival and apoptosis and identified BCLAF1, previously not described in atherosclerosis, as the most dysregulated gene. Functionally, BCLAF1 appeared to promote SMC survival by transdifferentiation into macrophage-like phenotype, by interacting with BCL2 and THRAP3.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.627
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1494427-3
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