| 1. |
- Krivospitskaya, Olesya, 1983-, et al.
(författare)
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A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
- 2012
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Ingår i: Molecular Medicine. - New York, USA : The Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 18:1, s. 712-718
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Tidskriftsartikel (refereegranskat)abstract
- All-trans retinoic acid, controlled by CYP26 enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26B1 in atherosclerosis and effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries and CYP26B1 and the macrophage marker CD68 co-localized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic than normal arteries. Databases were queried for non-synonymous CYP26B1 SNPs and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophage-like cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.
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| 2. |
- Paramel, Geena, 1985-, et al.
(författare)
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CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
- 2013
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Ingår i: Clinical Science. - London, United Kingdom : Portland Press. - 0143-5221 .- 1470-8736. ; 125:8, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.
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| 3. |
- Paramel, Geena, 1985-, et al.
(författare)
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Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
- 2013
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Ingår i: Biomedical reports. - : Spandidos Publications. - 2049-9434 .- 2049-9442. ; 1:6, s. 879-882
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome-related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First-ever myocardial Infarction study in Ac-county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single-nucleotide polymorphism assay. C-reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender-specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response.
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| 4. |
- Paramel Varghese, Geena, 1985-, et al.
(författare)
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NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
- 2016
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Ingår i: Journal of the American Heart Association. - Hoboken, USA : Wiley-Blackwell Publishing Inc.. - 2047-9980 .- 2047-9980. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.
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