Glycosaminoglycans as Key Molecules in Atherosclerosis: The Role of Versican and Hyaluronan

Karangelis, Dimos; Kanakis, Ioannis; Asimakopoulou, Antonia; Karousou, Evgenia; Passi, Alberto; Theocharis, Achilleas D.; Triposkiadis, Filippos; Tsilimingas, Nikolaos; Karamanos, Nikos K.

doi:10.2174/092986710793205354

Cited by 39 publications

(28 citation statements)

References 63 publications

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“…Previous studies suggest that HA is involved in endothelial proliferation and vascular changes (31,38). Therefore we investigated the potential relationship between the concentrations of HA in CSF and the CSF/serum albumin ratio (Q Alb), a crude indicator of BBB function.…”

Section: Correlations Between Csf Ha and Markers Of Inflammation And mentioning

confidence: 99%

“…Further, by binding to the cellsurface receptor CD44, HA recruits and activates leukocytes (29). Hyaluronic acid has also been described as a regulator of endothelial proliferation and blood vessel function (30) and it has become apparent that HA together with other adhesionmolecules, plays a key role in atherosclerosis (31). These finding together with the above mentioned links between inflammatory events, vascular changes and neurodegenerative diseases raise the question whether HA possibly could play a role in neurodegenerative dementia.…”

Section: Introductionmentioning

confidence: 99%

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Gender-Dependent Levels of Hyaluronic Acid in Cerebrospinal Fluid of Patients with Neurodegenerative Dementia

Nielsen¹,

Palmqvist²,

Minthon³

et al. 2012

CAR

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Numerous reports over the years have described neuroinflammatory events and vascular changes in neurodegenerative diseases such as Alzheimer´s disease (AD) and dementia with Lewy bodies (DLB). Interestingly, recent reports from other research areas suggest that inflammatory and vascular processes are influenced by gender. These findings are intriguing from the perspective that women show a higher incidence of AD and warrant investigations on how gender influences various processes in neurodegenerative dementia. In the current study we measured the cerebrospinal fluid (CSF) and plasma concentrations of hyaluroinic acid (HA), an adhesionmolecule known to regulate both vascular and inflammatory processes, in AD and DLB patients as well as in healthy elders. Our analysis showed that male AD and DLB patients had almost double the amount of HA compared to female patients whereas no gender differences were observed in the controls. Furthermore, we found that CSF levels of HA in foremost female AD patients correlated with various AD related biomarkers. Correlations between HA levels and markers of inflammation and vascular changes were only detected in female AD patients but in both male and female DLB patients. We conclude that HA may be linked to several pathological events present in AD, as reflected in CSF protein concentrations. The HA profile in CSF, but not in plasma, and associations to other markers appear to be genderdependent which should be taken into account in clinical examinations and future biomarker studies.

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Section: Correlations Between Csf Ha and Markers Of Inflammation And mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gender-Dependent Levels of Hyaluronic Acid in Cerebrospinal Fluid of Patients with Neurodegenerative Dementia

Nielsen¹,

Palmqvist²,

Minthon³

et al. 2012

CAR

View full text Add to dashboard Cite

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“…Cell type-specific sulfation balance is influenced by growth factor signaling and in turn can control cellular signaling pathways [7]–[11], [13], [14]. The specific sulfation pattern of CS chains dictates its function and binding affinities [7], [9], [15].…”

Section: Introductionmentioning

confidence: 99%

Chondroitin Sulfate-E Is a Negative Regulator of a Pro-Tumorigenic Wnt/Beta-Catenin-Collagen 1 Axis in Breast Cancer Cells

Willis

Klüppel

2014

PLoS ONE

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Expression of the glycosaminoglycan chondroitin sulfate-E (CS-E) is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt/beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt/beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt/beta-catenin - Collagen I axis.

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“…TIMP3 was selected for further study since the miR-712 interactome analysis (Figure 3a; Supplementary Figure S8) suggested its potential role as a key gene hub connected to numerous genes of interest, including matrix metalloproteinases-2/9 (MMP2/9) and a disintegrin and metalloproteinase 10/17 (ADAM10/17), ADAM with thrombospondin type 1 motif, 4 (ADAMTS4) and versican that are known to play a critical role in the regulation of vascular inflammation, permeability and atherosclerosis 23,24,25,26,27,28 .…”

Section: Mir-712 Targets Timp3 In the Endotheliummentioning

confidence: 99%

The atypical mechanosensitive microrna-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

Son

Kumar

2014

Atherosclerosis

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MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge Syndrome Critical Region-8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase-3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Author Contribution DJS and SK contributed equally to the manuscript. DJS, SK, WT, CN, JWS and KWF designed the experiments. DJS, SK, WT, CN, CW, JWS, SK, IHJ and NAG performed the experiments. DJS, WT, SK, CN, CWK, SOK, WKK, JWS, and NAG analyzed the data. AHB and KWF provided key reagents. SK, DJS, and HJ wrote the manuscript. HJ supervised the overall research, secured funding, designed experiments and interpreted results and wrote the manuscript. Accession codesThe microarray data have been deposited in NCBI's Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE52243.Conflict of Interest None. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same "seed sequence" as murine-specific miR-712, and also targets TIMP3 in a flowdependent manner. Targeting these mechanosensitive "athero-miRs" may provide a new treatment paradigm in atherosclerosis. HHS Public Access

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Glycosaminoglycans as Key Molecules in Atherosclerosis: The Role of Versican and Hyaluronan

Cited by 39 publications

References 63 publications

Gender-Dependent Levels of Hyaluronic Acid in Cerebrospinal Fluid of Patients with Neurodegenerative Dementia

Gender-Dependent Levels of Hyaluronic Acid in Cerebrospinal Fluid of Patients with Neurodegenerative Dementia

Chondroitin Sulfate-E Is a Negative Regulator of a Pro-Tumorigenic Wnt/Beta-Catenin-Collagen 1 Axis in Breast Cancer Cells

The atypical mechanosensitive microrna-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

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