| 1. |
- Mattsson Hultén, Lillemor, 1951, et al.
(författare)
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15-Lipoxygenase-2 is expressed in macrophages in human carotid plaques and regulated by hypoxia-inducible factor-1 alpha
- 2010
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 1365-2362 .- 0014-2972. ; 40:1, s. 11-17
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Tidskriftsartikel (refereegranskat)abstract
- Background Macrophages are prominent in hypoxic areas of atherosclerotic lesions and their secreted cytokines, growth factors and activity of enzymes are involved in atherogenesis. Previously, we showed that 15-lipoxygenase (LOX)-2 is expressed in human monocyte-derived macrophages and that hypoxia increases 15-LOX-2 expression and secretion of pro-inflammatory molecules. Here we investigated whether human carotid plaque macrophages express 15-LOX-2 and whether its expression in macrophages is regulated by hypoxia through hypoxia-inducible factor 1α (HIF-1α). Materials and methods Carotid plaques from 47 patients with high-grade symptomatic carotid artery stenosis were analysed using immunohistochemistry, and stained areas were quantified by digital image analysis. Carotid plaque macrophages were isolated with anti-CD14 immunobeads using an immunomagnetic bead technique. Primary macrophages were transfected with HIF-1α siRNA or control siRNA before extraction of RNA and medium analysis. Results In paired tissue sections, the extent of staining for CD68 correlated with staining for 15-LOX-2 but not for 15-LOX-1. In carotid plaque macrophages isolated with anti-CD14 immunobeads, 15-LOX-2 mRNA was expressed at high levels. In primary macrophages, 15-LOX-2 expression was significantly increased by incubation with the HIF-1α stabilizer dimethyloxalylglycine. Knockdown of HIF-1α significantly decreased production of the 15-LOX-2 enzyme products 12- and 15-hydroxyeicosatetraenoic acid. In carotid plaques, HIF-1α staining correlated with staining for 15-LOX-2. Conclusions These results demonstrate that 15-LOX-2 is highly expressed in human plaques and is correlated with the presence of macrophages and HIF-1α. 15-LOX-2 enzyme activity can be modulated by HIF-1α. Thus, increased expression of 15-LOX-2 in macrophages in hypoxic atherosclerotic plaque may enhance inflammation and the recruitment of inflammatory cells.
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| 2. |
- Olson, Fredrik J., 1975, et al.
(författare)
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Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis.
- 2008
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 263:6, s. 626-35
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. SUBJECTS AND DESIGN: Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. SETTING: Research unit at university hospital. RESULTS: Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. CONCLUSIONS: Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.
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| 3. |
- Olson, Fredrik J., 1975, et al.
(författare)
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Up- and downstream structural differences in carotid plaque composition - implications for studies of human symptomatic carotid plaques
- 2008
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Ingår i: Atherosclerosis Supplements. - 1567-5688. ; 9:1
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Konferensbidrag (refereegranskat)abstract
- Background and aims: Blood passing a protruding plaque causes high laminar shear stress at the upstream shoulder with increased risk of rupture, whereas blood flow is turbulent causing low shear stress at the downstream shoulder, where plaque growth generally occurs. Low shear stress induces cell adhesion, inflammation and apoptosis. Cap shoulders are of key interest in the mechanisms leading to development of rupture-prone plaques. Our aim was to explore morphology and composition of human carotid endarterectomies in up- and downstream parts, and to relate the occurrence of macrophages in shoulder regions to that in the entire plaque. Methods: Endarterectomies from 87 patients with symptomatic carotid atherosclerosis were divided transversely into 3mm pieces (4-18 paraffin-embedded pieces/plaque). Sections were prepared and histologically classified for plaque vulnerability features: AHA classification, thin cap, plaque rupture, and surface thrombosis; and were also immunohistochemically stained for macrophages and other components. Clinical information was collected, to correlate results with clinical history and risk factors. Results: On average, the most stenotic part of the plaque was 3mm into the internal carotid artery, from the bifurcation. Plaque vulnerability features were most prevalent at this level, and were less frequent in distal sections upstream. Macrophage content was higher downstream of the stenosis than in upstream parts. The shoulder regions contained less than 10% of all macrophages. Conclusions: Upstream and downstream parts of human symptomatic carotid atherosclerotic plaques differed significantly in morphology and composition. Only a small fraction of macrophages in the plaques were located in the cap shoulder regions.
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| 4. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Urokinase-type plasminogen activator receptor is associated with macrophages and plaque rupture in symptomatic carotid atherosclerosis.
- 2008
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Ingår i: International journal of molecular medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 22:4, s. 459-64
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Tidskriftsartikel (refereegranskat)abstract
- There is a strong correlation between macrophage infiltration and plaque instability in recently symptomatic carotid atherosclerotic plaques, and it is hypothesised that mechanisms related to macrophages may be involved in plaque vulnerability and rupture. We previously found high expression of urokinase-type plasminogen activator receptor (UPAR) in human macrophages. The aim of this study was to investigate whether UPAR co-localises with macrophages in symptomatic carotid plaques, and whether UPAR expression is associated with plaque rupture. Real-time RT-PCR assays showed that UPAR expression levels were high in monocyte-derived macrophages and in carotid endarterectomies compared with a tissue panel. Serial transverse sections were prepared from carotid endarterectomies from 12 symptomatic patients, and analyzed with immunohistochemical staining for UPAR and for CD68-positive macrophages, and with histopathological assessment. UPAR co-localised with CD68-positive macrophages, with a high correlation (r=0.90, p<0.001) between immunostained areas in 12 carotid endarterectomies from symptomatic patients. High degrees of UPAR and CD68 staining were found in sections around the bifurcation level where rupture was most common, while low degrees of staining were found in sections of the common carotid artery end of the endarterectomy (p<0.05). Higher degrees of UPAR staining were observed in ruptured plaque sections compared with non-ruptured sections. In conclusion, UPAR was highly expressed in monocyte-derived macrophages and in symptomatic carotid plaques, UPAR co-localised with macrophages in carotid symptomatic plaques and UPAR was predominantly found in ruptured plaque segments. These findings support the hypothesis that UPAR is related to plaque rupture in symptomatic atherosclerotic lesions.
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