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The extracellular m...
The extracellular matrix proteoglycan serglycin is associated with human atherosclerotic plaque inflammation
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- Gialeli, C. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Fountas, P. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Shami, A. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Sun, J. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Bocci, M. (author)
- Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden
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- Nitulescu, M. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Persson, A. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Bengtsson, Eva (author)
- Malmö universitet,Institutionen för biomedicinsk vetenskap (BMV),Lund Univ, Dept Clin Sci, Malmö, Sweden
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- Knutsen, E. (author)
- UiT Arctic Univ Norway, Fac Hlth Sci, Dept Med Biol, Tromsø, Norway
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- Pietras, K. (author)
- Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden
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- Theocharis, A. (author)
- Univ Patras, Dept Chem, Biochem Biochem Anal & Matrix Pathobiol Res Grp, Patras, Greece
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- Edsfeldt, A. (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden; Skåne Univ Hosp, Dept Cardiol, Malmö, Sweden
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- Goncalves, I (author)
- Lund Univ, Dept Clin Sci, Malmö, Sweden; Skåne Univ Hosp, Dept Cardiol, Malmö, Sweden
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(creator_code:org_t)
- Oxford University Press, 2024
- 2024
- English.
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 120:S1
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Abstract
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- Background: Atherosclerotic cardiovascular disease is caused by the formation of plaques in the arterial wall which contain lipids, cells, cell debris and a unique extracellular matrix (ECM) signature. These plaques may ultimately rupture or erode away causing thrombosis, thereby leading to myocardial infarction or stroke. Rupture-prone plaques generally bear a greater inflammatory activity, with ECM proteins suggested to influence the inflammatory activity. Among many ECM proteins, serglycin (SRGN) is highly expressed by inflammatory cells, and SRGN has been linked to modulation of the inflammatory response in disease such as cancer. Yet, if SRGN contributes to the inflammatory circuitry in human atherosclerotic plaques remains to be explored.Purpose: We aimed to investigate if SRGN was associated with inflammation in atherosclerotic plaques.Methods: Plaque protein levels of SRGN were measured by ELISA in human carotid plaques obtained from the Carotid Plaque Imaging Project (CPIP) biobank. Plaque RNA expression levels of SRGN and cell markers were assessed by plaque bulk RNA sequencing. SRGN expression and distribution were further examined in tissue plaque sections through histology and multispectral imaging. In vitro models were used to investigate the functional consequences of SRGN expression changes, using SRGN CRISPR knockout THP1 monocytic cells. Immunoprecipitation of SRGN and immunoblotting against SRGN, heparan and chondroitin sulfate chains were employed to structurally characterize plaque protein SRGN.Results: SRGN protein levels were significantly higher in plaques from asymptomatic patients compared to symptomatic. Multispectral imaging showed that SRGN protein was observed in plaque areas rich in macrophages and lipids. Using immunoprecipitation and immunoblotting, we identified a unique low glycosylated plaque SRGN, with both heparan sulfate and chondroitin sulfate glycosaminoglycans decorating its protein core. This exclusive configuration suggests that the plaque cell origin of SRGN may be macrophages or mast cells. In support of this, plaque SRGN RNA expression correlated with RNA levels of pro-inflammatory macrophage cells markers like CD68, CD163, MRC1, ITGAX. Plaque SRGN protein levels correlated with plaque levels of oxidised lipoproteins, proatherogenic (CCL1, IL7, MCP-4 and TNFα) and antiatherogenic cytokines (IL33, IL16 and CXCL13), as well as with growth factors, such as TGF-β. On the one hand, in vitro suppression of SRGN expression in monocytes led to a reduction in the anti-inflammatory M2-polarized phenotype, while M1 pro-inflammatory macrophages were unskewed. Furthermore, our in vitro studies showed that upon SRGN knockdown M2 macrophages retained more oxidized lipoproteins.Conclusions: Our results suggest that SRGN may be a crucial modulator of inflammation in human atherosclerotic plaques, potentially by affecting the bioavailability of effector molecules such as growth factors and cytokines.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
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- By the author/editor
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Gialeli, C.
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Fountas, P.
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Shami, A.
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Sun, J.
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Bocci, M.
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Nitulescu, M.
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show more...
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Persson, A.
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Bengtsson, Eva
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Knutsen, E.
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Pietras, K.
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Theocharis, A.
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Edsfeldt, A.
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Goncalves, I
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cardiac and Card ...
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Cardiovascular R ...
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Malmö University