Increased expression of heparanase in symptomatic carotid atherosclerosis

Österholm, Cecilia; Folkersen, Lasse; Lengquist, Mariette; Pontén, Fredrik; Renné, Thomas; Li, Jinping; Hedin, Ulf

doi:10.1016/j.atherosclerosis.2012.09.030

Cited by 50 publications

(46 citation statements)

References 31 publications

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“…Previously, MMPs have been assigned a key role in plaque remodeling, 43 while we recently demonstrated increased expression of Heparanase in symptomatic carotid lesions. 18 Here, we also observed a colocalization between PCSK6 and heparan sulfate, which is in agreement with the unique features of this protease to anchor in the ECM by binding to heparan-sulfate proteoglycans. 41,42 Because heparan-sulfate proteoglycans such as perlecan can take part in the control of SMC proliferation, 44,45 the association between PCSK6, heparan sulfate, and Heparanase suggests that PCSK6 may be involved in the regulation of SMC growth in atherosclerosis.…”

Section: Discussionsupporting

confidence: 90%

“…16,17 The application of TMA technology in this type of vascular disease analyses places our study among the very few that have attempted the same. 18 By this approach, we demonstrated upregulation of genes involved in inflammation, lipid metabolism, cell proliferation, and coagulation in symptomatic compared with asymptomatic carotid plaques, as well as differential expression of several proteins. PCSK6, a proprotein convertase (PC) previously not associated with atherosclerosis, was shown to be highly upregulated in symptomatic plaques both at the mRNA and protein levels, and predominantly expressed by SMCs of the fibrous cap.…”

mentioning

confidence: 87%

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Profiling of Atherosclerotic Lesions by Gene and Tissue Microarrays Reveals PCSK6 as a Novel Protease in Unstable Carotid Atherosclerosis

Perisic

Hedin

Razuvaev

et al. 2013

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Objective— Carotid plaque instability is a major cause of ischemic stroke, but detailed knowledge about underlying molecular pathways is still lacking. Here, we evaluated large-scale transcriptomic and protein expression profiling in a biobank of carotid endarterectomies followed by characterization of identified candidates, as a platform for discovery of novel proteins differentially regulated in unstable carotid lesions. Approach and Results— Genes highly upregulated in symptomatic versus asymptomatic plaques were selected from Affymetrix microarray analyses (n=127 plaques), and tissue microarrays constructed from 34 lesions were assayed for 21 corresponding proteins by immunohistochemistry. Quantification of stainings demonstrated differential expression of CD36, CD137, and DOCK7 ( P <0.05) in unstable versus stable lesions and the most significant upregulation of a proprotein convertase, PCSK6 ( P <0.0001). Increased expression of PCSK6 in symptomatic lesions was verified by quantitative real-time polymerase chain reaction (n=233), and the protein was localized to smooth muscle α-actin positive cells and extracellular matrix of the fibrous cap by immunohistochemistry. PCSK6 expression positively correlated to genes associated with inflammation, matrix degradation, and mitogens in microarrays. Stimulation of human carotid smooth muscle cells in vitro with cytokines caused rapid induction of PCSK6 mRNA. Conclusions— Using a combination of transcriptomic and tissue microarray profiling, we demonstrate a novel approach to identify proteins differentially expressed in unstable carotid atherosclerosis. The proprotein convertase PCSK6 was detected at increased levels in the fibrous cap of symptomatic carotid plaques, possibly associated with key processes in plaque rupture such as inflammation and extracellular matrix remodeling. Further studies are needed to clarify the role of PCSK6 in atherosclerosis.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 87%

Profiling of Atherosclerotic Lesions by Gene and Tissue Microarrays Reveals PCSK6 as a Novel Protease in Unstable Carotid Atherosclerosis

Perisic

Hedin

Razuvaev

et al. 2013

ATVB

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“…It is conceivable that Sulfs or other HSPG modifying enzymes, such as matrix metalloproteases and heparanase, a heparan-degrading enzyme, might modulate the bioavailability of IFN-β in the macrophage microenvironment in a similar way. While we did no observe differences in heparanase expression in macrophages, increased heparanase expression has been linked to activation of innate immune cells, expression of inflammatory markers, such as CCL5, CCL2 and TNF-α, and plaque vulnerability (Blich et al, 2013; Osterholm et al, 2013). …”

Section: Discussioncontrasting

confidence: 82%

“…The amazing sensitivity of this system to small changes in the degree of sulfation of HS induced by Ndst1 inactivation suggests that normal variation in the structure of HS could make some individuals more prone to macrophage priming and activation and downstream sequelae related to chronic inflammation (Shao et al, 2013; Wei et al, 2011). HS content and sulfation is decreased in advanced atherosclerotic lesions when compared to early lesions (Hollmann, 1989; Murata et al, 1997) and a recent study revealed a positive correlation for heparanase expression in human vulnerable plaques with expression of inflammatory markers as CCL5, CCL2 and TNF-α (Osterholm et al, 2013). Our data warrant further analysis of macrophage HS and allelic variants of genes involved in HS metabolism in order to determine whether HSPG alterations have predictive value with respect to cardiovascular disease and obesity.…”

Section: Discussionmentioning

confidence: 99%

Reducing Macrophage Proteoglycan Sulfation Increases Atherosclerosis and Obesity through Enhanced Type I Interferon Signaling

et al. 2014

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Summary Heparan sulfate proteoglycans (HSPGs) are an important constituent of the macrophage glycocalyx and extracellular microenvironment. To examine their role in atherogenesis, we inactivated the biosynthetic gene N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1) in macrophages and crossbred the strain to Ldlr−/− mice. When placed on an atherogenic diet, Ldlr−/−Ndst1f/fLysMCre+ mice had increased atherosclerotic plaque area and volume compared to Ldlr−/− mice. Diminished sulfation of heparan sulfate resulted in enhanced chemokine expression, increased macrophages in plaques, increased expression of ACAT2, a key enzyme in cholesterol ester storage, and increased foam cell conversion. Motif analysis of promoters of up-regulated genes suggested increased Type I Interferon signaling, which was confirmed by elevation of STAT1 phosphorylation induced by IFN-β. The pro-inflammatory macrophages derived from Ndst1f/fLysMCre+ mice also sensitized the animals to diet-induced obesity. We propose that macrophage HSPGs control basal activation of macrophages by maintaining Type I interferon reception in a quiescent state through sequestration of IFN-β.

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“…Many studies of novel target genes in atherosclerosis using data from the BiKE have already been reported [21,23,24,29]. Here, the analysis revealed additional genes that had not previously been associated with atherosclerosis, of which several were selected for replication in a nonoverlapping set of patients.…”

Section: Discussionmentioning

confidence: 87%

Gene expression signatures, pathways and networks in carotid atherosclerosis

et al. 2015

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Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis.

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Increased expression of heparanase in symptomatic carotid atherosclerosis

Cited by 50 publications

References 31 publications

Profiling of Atherosclerotic Lesions by Gene and Tissue Microarrays Reveals PCSK6 as a Novel Protease in Unstable Carotid Atherosclerosis

Profiling of Atherosclerotic Lesions by Gene and Tissue Microarrays Reveals PCSK6 as a Novel Protease in Unstable Carotid Atherosclerosis

Reducing Macrophage Proteoglycan Sulfation Increases Atherosclerosis and Obesity through Enhanced Type I Interferon Signaling

Gene expression signatures, pathways and networks in carotid atherosclerosis

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