| 1. |
- Edsfeldt, Andreas, et al.
(författare)
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Soluble Urokinase Plasminogen Activator Receptor is Associated With Inflammation in the Vulnerable Human Atherosclerotic Plaque.
- 2012
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:12, s. 3305-3312
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Tidskriftsartikel (refereegranskat)abstract
- Recently, plasma soluble urokinase plasminogen activator receptor (suPAR) has gained interest as a marker of cardiovascular risk. suPAR is released through the cleavage of urokinase plasminogen activator receptor (uPAR), which is found in monocytes, activated T-lymphocytes and endothelial cells, all involved in atherosclerosis. suPAR levels have been well studied in plasma, but no studies have focused on suPAR in human atherosclerotic plaques. The aim of this study was to determine whether suPAR measured in the plaque is associated with symptomatic plaques and plaque inflammation.
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| 2. |
- Asciutto, Giuseppe, et al.
(författare)
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Low elastin content of carotid plaques is associated with increased risk of ipsilateral stroke.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic plaques with a low content of connective tissue proteins are believed to have an increased risk of rupture and to give rise to clinical events. The aim of the present study was to investigate if the content of elastin, collagen and of the matrix metalloproteinase (MMP) -1, -3, -9 and -12 in plaques removed at surgery can be associated with the occurrence of ipsilateral symptoms.
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| 3. |
- Bengtsson, Eva, et al.
(författare)
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CD163+ macrophages are associated with a vulnerable plaque phenotype in human carotid plaques
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages are a functionally heterogeneous group of immune cells abundant in atherosclerotic plaques. Macrophages expressing CD163 are associated with intraplaque hemorrhage and have previously been considered atheroprotective. However, in a recent study CD163-deficient atherosclerotic ApoE−/− mice exhibited smaller and less complex plaques, suggesting a proatherogenic role of CD163. Previous smaller studies on CD163+ macrophages and plaque stability in humans have yielded diverging results. Here we assessed the association of CD163+ cells to plaque vulnerability in a large cohort of human carotid plaques. CD163 protein expression was analyzed by immunohistochemistry in 200 human carotid plaques removed by endarterectomy from 103 patients with and 93 patients without cerebrovascular symptoms. Furthermore, CD163 mRNA expression was analyzed in 66 of the plaques. Both protein and mRNA expression of CD163 was higher in plaques from symptomatic patients and in plaques with high vulnerability index. CD163+ macrophages were primarily found in shoulder regions and in the center of the plaques. The present data show that CD163 is associated with increased plaque vulnerability in human carotid plaques, supporting the notion that CD163+ macrophages could contribute to clinical events.
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| 4. |
- Edsfeldt, Andreas, et al.
(författare)
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Circulating cytokines reflect the expression of pro-inflammatory cytokines in atherosclerotic plaques.
- 2015
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 241:2, s. 443-449
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key factor in the development of plaque rupture and acute cardiovascular events. Although imaging techniques can be used to identify vulnerable atherosclerotic plaques, we are lacking non-invasive methods, such as plasma markers of plaque inflammation that could help to identify presence of vulnerable plaques. The aim of the present study was to investigate whether increased plasma levels of pro-inflammatory cytokines reflects inflammatory activity within atherosclerotic plaques.
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| 5. |
- Edsfeldt, Andreas, et al.
(författare)
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Impaired Fibrous Repair: A Possible Contributor to Atherosclerotic Plaque Vulnerability in Patients With Type II Diabetes.
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 34:9, s. 2143-2150
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) type II is increasing rapidly worldwide. Patients with DM II have a greater atherosclerotic burden and higher risk of developing cardiovascular complications. Inflammation has been proposed as the main cause for the high risk of atherosclerotic disease in DM II. In this study, we compared markers of inflammation and fibrous repair in plaques from subjects with and without DM II.
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| 6. |
- Edsfeldt, Andreas, et al.
(författare)
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Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 43:19, s. 1864-1877
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Inflammation is a key factor in atherosclerosis. The transcription factor interferon regulatory factor-5 (IRF5) drives macrophages towards a pro-inflammatory state. We investigated the role of IRF5 in human atherosclerosis and plaque stability.METHODS AND RESULTS: Bulk RNA sequencing from the Carotid Plaque Imaging Project biobank were used to mine associations between major macrophage associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were used for validation. The effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE-/- mice was studied in an inducible model of plaque rupture. Interferon regulatory factor-5 and ITGAX/CD11c were identified as the macrophage associated genes with the strongest associations with symptomatic carotid disease. Expression of IRF5 and ITGAX/CD11c correlated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and with each other. Macrophages were the predominant CD11c-expressing immune cells in the plaque by CyTOF and immunohistochemistry. Interferon regulatory factor-5 immunopositive areas were predominantly found within CD11c+ areas with a predilection for the shoulder region, the area of the human plaque most prone to rupture. Accordingly, an inducible plaque rupture model of ApoE-/-Irf5-/- mice had significantly lower frequencies of carotid plaque ruptures, smaller necrotic cores, and less CD11c+ macrophages than their IRF5-competent counterparts.CONCLUSION: Using complementary evidence from data from human carotid endarterectomies and a murine model of inducible rupture of carotid artery plaque in IRF5-deficient mice, we demonstrate a mechanistic link between the pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and its vulnerability to rupture.KEY QUESTION: The transcription factor interferon regulatory factor-5 (IRF5) is a master regulator of macrophage activation that has been shown to have a role in murine atherogenesis. Its role in human atherosclerosis and its complications is unknown.KEY FINDING: Interferon regulatory factor-5 is linked to plaque vulnerability and symptoms in human carotid endarterectomies. In a murine model of inducible carotid artery plaque rupture, IRF5 drives plaque rupture. Interferon regulatory factor-5 modulates macrophage phenotype and it colocalises with CD11c+ macrophages at the plaque shoulder.TAKE-HOME MESSAGE: We demonstrate a mechanistic link between the IRF5, plaque macrophages, and plaque vulnerability to rupture. Interferon regulatory factor-5 is a potential candidate therapeutic target in human atherosclerosis.
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| 7. |
- Edsfeldt, Andreas, et al.
(författare)
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Low carotid calcium score is associated with higher levels of glycosaminoglycans, tumor necrosis factor-alpha, and parathyroid hormone in human carotid plaques.
- 2011
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 42:10, s. 458-2966
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Computed tomography (CT) is used to study coronary artery plaques, but little is known about its potential to characterize plaque composition. This study assesses the relation between carotid calcium score (CCS) by CT and plaque composition, namely extracellular matrix, inflammatory mediators, and calcium metabolites. METHODS: Thirty patients with significant carotid stenosis underwent preoperative CT. CCS was quantified by Agaston calcium score. Plaque components were studied histologically and biochemically (collagen, elastin, and glycosaminoglycans). Fraktalkine, interferon-γ, interleukin-10, interleukin-12 p70, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, platelet-derived growth factor-AB/BB, RANTES and tumor necrosis factor-α, and parathyroid hormone were measured using Luminex technology. RESULTS: Plaques with CCS ≥400 had more calcium (P=0.012), less glycosaminoglycan (P=0.002), tumor necrosis factor-α (P=0.013), and parathyroid hormone (P=0.028) than those with CCS <400. CCS correlated with plaque content of calcium (r=0.62; P<0.001) and inversely with glycosaminoglycan (r=-0.49; P=0.006) and tumor necrosis factor-α (r=-0.56; P=0.001). CONCLUSIONS: Human carotid plaques with high CCS are richer in calcium and have lower amounts of glycosaminoglycan, parathyroid hormone, and tumor necrosis factor-α, which is one of the main proinflammatory cytokines involved in atherosclerosis. This suggests that CCS not only reflects the degree of calcification, but also other important biological components relevant for stability such as inflammation.
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| 8. |
- Edsfeldt, Andreas, et al.
(författare)
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Proinflammatory Role of Sphingolipids and Glycosphingolipids in the Human Atherosclerotic Plaque
- 2016
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 36:6, s. 1132-1140
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Lipids are central to the development of atherosclerotic plaques. Specifically, which lipids are culprits remains controversial, and promising targets have failed in clinical studies. Sphingolipids are bioactive lipids present in atherosclerotic plaques, and they have been suggested to have both proatherogenic and antiatherogenic. However, the biological effects of these lipids remain unknown in the human atherosclerotic plaque. The aim of this study was to assess plaque levels of sphingolipids and investigate their potential association with and contribution to plaque vulnerability.APPROACH AND RESULTS: Glucosylceramide, lactosylceramide, ceramide, dihydroceramide, sphingomyelin, and sphingosine-1-phosphate were analyzed in homogenates from 200 human carotid plaques using mass spectrometry. Inflammatory activity was determined by analyzing plaque levels of cytokines and plaque histology. Caspase-3 was analyzed by ELISA technique. Expression of regulatory enzymes was analyzed with RNA sequencing. Human coronary artery smooth muscle cells were used to analyze the potential role of the 6 sphingolipids as inducers of plaque inflammation and cellular apoptosis in vitro. All sphingolipids were increased in plaques associated with symptoms and correlated with inflammatory cytokines. All sphingolipids, except sphingosine-1-phosphate, also correlated with histological markers of plaque instability. Lactosylceramide, ceramide, sphingomyelin, and sphingosine-1-phosphate correlated with caspase-3 activity. In vitro experiments revealed that glucosylceramide, lactosylceramide, and ceramide induced cellular apoptosis. All analyzed sphingolipids induced an inflammatory response in human coronary artery smooth muscle cells.CONCLUSIONS: This study shows for the first time that sphingolipids and particularly glucosylceramide are associated with and are possible inducers of plaque inflammation and instability, pointing to sphingolipid metabolic pathways as possible novel therapeutic targets.
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| 9. |
- Gonçalves, Isabel, et al.
(författare)
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Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes
- 2016
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 16:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.
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| 10. |
- Goncalves, Isabel, et al.
(författare)
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Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.
- 2015
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:7, s. 1723-1731
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
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