| 1. |
- Hägg, Daniel, 1974, et al.
(författare)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 21:6, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 2. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Gene expression in human brown adipose tissue.
- 2011
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Ingår i: International journal of molecular medicine. - : Spandidos Publications. - 1791-244X .- 1107-3756. ; 27:2, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) has profound effects on body weight and metabolism in rodents. Recent reports show that human adults have significant amounts of BAT. Our aim was to study the gene expression profile of human BAT. Biopsies of adipose tissue with brown-red color and subcutaneous white adipose tissue (WAT) were obtained from 24 patients undergoing surgery in the thyroid region. Intrascapular BAT and epididymal WAT biopsies were obtained from 10 mice. Expression was analyzed by DNA microarray, real-time PCR and immunohistochemistry. Using the expression of the brown adipocyte-specific gene uncoupling protein 1 (UCP1) as a marker, approximately half of the human brown-red adipose tissue biopsies taken in the thyroid region contained BAT, and the presence of cells with brown adipocyte morphology was also verified by histology. Microarray analysis of 9 paired human BAT and WAT samples showed that 17 genes had at least a 4-fold higher expression in BAT compared to WAT and five of them (CKMT1, KCNK3, COBL, HMGCS2, TGM2) were verified using real-time PCR (P<0.05 for all). In addition, immunohistochemistry showed that the UCP1, KCNK3 and CKMT1 proteins are expressed in brown adipocytes. Except for UCP1 and KCNK3, the genes overexpressed in human BAT were not overexpressed in mouse BAT compared to mouse WAT. Our analysis identified genes that are differentially expressed in human BAT compared to WAT. The results also show that there are species-specific differences in BAT gene expression and this emphasizes the need for further molecular characterization of human BAT to clarify the mechanisms involved in regulated heat production in humans.
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| 3. |
- 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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