Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization
Author: Karlöf, Eva; Seime, Till; Dias, Nuno; Lengqvist, Mariette; Witasp, Anna; Almqvist, Håkan; Kronqvist, Malin; Gådin, Jesper Robert; Odeberg, Jacob; Maegdefessel, Lars; Stenvinkel, Peter; Matic, Ljubica Perisic; Hedin, Ulf
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
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Abstract
Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions.
Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients.
Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells.
Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.
Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients.
Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells.
Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.
Institution:
- Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Vascular Center, Department of Vascular Surgery, Skåne University Hospital, Malmö, Sweden
- Division of Renal Medicine, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Department of Proteomics, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
Citation: Atherosclerosis. 2019 Sep;288:175-185.
Citation DOI: 10.1016/j.atherosclerosis.2019.05.005
Citation PMID: 31109707
Citation ISI: 000485127200025
Publishing journal: Atherosclerosis
Eprint status: Peer Reviewed
Version: Published
Issue date: 2021-02-24
Sponsorship:
- European Union’s Horizon 2020/Marie Sklodowska-Curie, 722609 (INTRICARE)
- Swedish Heart and Lung Foundation
- Swedish Research Council, K2009-65X-2233-01-3, K2013- 65X-06816-30-4, 349-2007-8703
- Uppdrag Besegra Stroke, P581/ 2011-123
- Stockholm County Council, ALF2011-0260, ALF-2011- 0279
- Swedish Society for Medical Research
- Tore Nilsson’s Foundation
- Magnus Bergvall’s Foundation
- Karolinska Institutet Foundation
- European Commission, 722609
Rights:
CC BY-NC-ND 4.0
Publication year: 2019
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