| 1. |
- Mälarstig, Anders, et al.
(författare)
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Raised Interleukin-10 is an Indicator of Poor Outcome and Enhanced Systemic Inflammation in Patients with Acute Coronary Syndrome
- 2008
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 94:6, s. 724-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To re-evaluate the relation between plasma interleukin-10 (IL-10) concentration at hospital admission and outcome and to investigate the impact of single nucleotide polymorphisms (SNP) in the IL-10 gene in patients with non-ST elevation acute coronary syndrome (ACS). DESIGN: Determination of IL-10 plasma concentrations and genotyping of SNPs in the IL-10 gene in a prospective trial of patients with ACS and in a group of healthy controls. PATIENTS: 3179 patients in the Fragmin and fast revascularisation during InStability in Coronary artery disease II (FRISC II) trial and 393 healthy controls. MAIN OUTCOME MEASURES: Mortality and incidence of myocardial infarction (MI) at 12 months. RESULTS: The median and interquartile ranges of IL-10 were 0.8 (0.5-1.0) pg/ml in healthy controls and 1.1 (0.7-1.9) pg/ml in patients (p<0.001). In patients, IL-10 predicted a crude risk increase of death/MI, with the highest risk observed in the fourth quartile (adjusted odds ratio 1.7 (95% confidence interval 1.2 to 2.3)). Adjustment for common risk indicators, including C-reactive protein and interleukin-6, weakened the association to a non-significant level. The 1170 CC genotype weakly predicted increased plasma concentrations of IL-10 in patients (p = 0.04) and in controls (p = 0.03), which was consistent with the modest association of this variant with coronary disease (p = 0.01). CONCLUSION: In contrast with some previous reports, we conclude that IL-10 reflects a proinflammatory state in patients with ACS and we therefore suggest that IL-10 is as effective a biomarker for the risk prediction of future cardiovascular events as other markers of systemic inflammation.
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| 2. |
- Mälarstig, Anders, et al.
(författare)
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Variants of the interferon regulatory factor 5 gene regulate expression of IRF5 mRNA in atherosclerotic tissue but are not associated with myocardial infarction
- 2008
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 28:5, s. 975-982
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Signaling events after activation of toll-like receptors (TLRs) are important mechanisms promoting inflammation in the atherosclerotic plaque. INF regulatory factor 5 (IRF5) is one of the mediators of downstream effects of TLRs. Several single nucleotide polymorphisms (SNPs) in the IRF5 gene have been found to be associated with systemic lupus erythematosus. METHODS AND RESULTS: We examined IRF5 mRNA expression in carotid atherosclerotic tissue (n=99) and the case-control association between SNPs in the IRF5 gene with myocardial infarction (MI) (n=376+387) and unstable coronary artery disease (CAD) (n=3101+445). Among unstable CAD patients, association of IRF5 SNPs with recurrent coronary events (n=401) was also investigated. The IRF5 mRNA expression was increased in atherosclerotic tissue compared with control tissue (P<0.001). Significant associations with IRF5 expression was observed for 6 of 10 SNPs in the study. However, the IRF5 SNPs examined were neither associated with the risk of precocious MI, nor with unstable CAD or risk of recurrent cardiovascular events in unstable CAD patients. CONCLUSIONS: IRF5 mRNA is expressed in cells in atherosclerotic tissue and its expression is modified by SNPs in the IRF5 gene. Genetic variation at the IRF5 locus was, however, not associated with CAD or related phenotypes.
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| 3. |
- 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. ; 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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| 4. |
- Sjogren, Per, et al.
(författare)
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High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 29:18, s. 2218-2226
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Tidskriftsartikel (refereegranskat)abstract
- Aims We examined whether antibodies against peptides 45 and 210 of apoB-100 are related to myocardial infarction (MI) and severity of coronary atherosclerosis. Methods and results Three hundred and eighty-seven survivors of a first MI (aged < 60 years) and 387 sex- and age-matched controls were characterized in detail. IgG and IgM autoantibodies against native and malondialdehyde (MDA)-modified peptides 45 and 210 of apoB-100 (amino acids 661-680 and 3136-3155) were quantified in plasma and quantitative coronary angiography was performed in 243 patients. Post-infarction patients had significantly lower IgG against the native peptide 210 (IgG-p210(nat)) and higher IgM against the MDA-modified peptide 210 (IgM-p210(MDA)) compared with controls, whereas no differences were found for other antibodies. Plasma concentrations of IgG-p210(nat), but not IgM-p210(MDA), were independently and inversely related to the degree of coronary atherosclerosis in patients. In multiple logistic regression analysis (including established risk indicators), MI risk was 0.55 (95%CI: 0.37-0.81) for individuals in the IgG-p210(nat) upper quartile compared with the remaining individuals. Conclusion Circulating IgG antibodies against the native peptide 210 of apoB-100 are inversely related to the severity of coronary atherosclerosis and associated with lower risk of MI. Epitope 210 of apoB-100 emerges as a target for immunization against atherosclerosis in humans.
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| 5. |
- Sjögren, Per, et al.
(författare)
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Autoantibodies against modified apolipoprotein B-100 in relation to low-density lipoprotein size and the metabolic syndrome in otherwise healthy men
- 2008
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 57:3, s. 362-366
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Tidskriftsartikel (refereegranskat)abstract
- The role of inflammation in atherosclerotic disease is well established, but the role of autoantibodies against modified apolipoprotein (apo) B-100 remains unclear. The metabolic syndrome is associated with a proinflammatory state, a predominance of small dense low-density lipoprotein (LDL) particles, and an increased risk for atherosclerotic diseases. Previous studies have shown specific autoantibodies against modified apo B-100 (within LDL) to be related to human atherosclerotic disease. The objective of the present study was to investigate whether autoantibodies against modified apo B-100 are related to parameters of the metabolic syndrome, such as small dense LDL. Two hundred ninety-one healthy men were investigated for different metabolic, anthropometric, and inflammatory variables; LDL peak particle size; and distribution of LDL in 4 subfractions. Subjects were grouped according to LDL peak size >= 23.5 nm (pattern A, n = 230) or <23.5 nm (pattern B, n = 61). Immunoglobulin (Ig) G and IgM antibodies against 2 aldehyde-modified peptide sequences, denoted as 45 and 210, within apo B-100 were quantified. Levels of IgG(45), but not the other autoantibodies, were significantly higher in pattern B individuals (with a predominance of small dense LDL particles) compared with pattern A (P < .01). Relationships for both IgG(45) and IgG(210) with parameters typically associated with the metabolic syndrome were found. Only IgG(45) tended to be higher in individuals with the metabolic syndrome compared with those without (P = .07). We conclude that subjects with a predominance of small dense LDL particles have elevated concentrations of IgG(45) in the circulation, which reflect an activated immune response to a specific epitope of modified apo B-100.
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| 6. |
- Wågsäter, Dick, et al.
(författare)
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ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques
- 2008
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 196:2, s. 514-522
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:Remodeling of extracellular matrix (ECM) plays an important role in inflammatory disorders such as atherosclerosis. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently described family of proteinases that is able to degrade the ECM proteins aggrecan and versican expressed in blood vessels. The purpose of the present study was to analyze the expression and regulation of several ADAMTSs before and after macrophage differentiation and after stimulation with IFN-gamma, IL-1beta and TNF-alpha. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.METHODS AND RESULTS:Real time RTPCR showed that, of the nine different ADAMTS members examined, only ADAMTS-4 and -8 were induced during monocyte to macrophage differentiation, which was also seen at protein level. Macrophage expression of ADAMTS-4, -7, -8 and -9 mRNA were enhanced upon stimulation with IFN-gamma or TNF-alpha. Furthermore, immunohistochemical analyses revealed that ADAMTS-4 and -8 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. In addition, ADAMTS-4 expression was upregulated during the development of atherosclerosis in LDLR(-/-)ApoB(100/100) mice. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas, it was significantly higher in aortas from 30-40-week old atherosclerotic animals.CONCLUSION:The present study suggests that ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. This is the first study associating ADAMTS-4 and -8 expression with atherosclerosis. However, further experiments are required to understand the physiological and pathological functions of ADAMTS in the vascular wall, and tools to measure ADAMTS activity need to be developed.
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