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- Elmabsout, Ali Ateia, 1977-
(författare)
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CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease (CVD), currently the most common cause of morbidity and mortality worldwide, is caused mainly by atherosclerosis. Atherosclerosis is a chronic multifocal, immunoinflammatory, fibroproliferative disease of medium and large arteries. Atherosclerotic lesions and vascular cells express different genes, among these are genes regulated by retinoic acid. Retinoids have pleiotropic effects and are able to modulate gene expression involved in growth, function and adaptation. During atherosclerosis development, there is endothelial perturbation, lipid accumulation, attraction of immune cells, smooth muscle cell migration and extracellular matrix remodeling and eventually fibrous cap formation which results in plaques. Retinoids have been demonstrated to either inhibit or modulate the above processes, resulting in amelioration of atherosclerosis. So far, retinoids are known to have impact on cellular processes in SMC, vascular injury and atherosclerosis. However, little is known about catabolism of retinoids in vascular cells and lesions and the effects of alteration of retinoic catabolizing enzymes on retinoids’ status. Therefore, we investigated the expression of Cytochrome P450 26 (CYP26) which is thought to be dedicated to retinoid catabolism. In vascular SMCs and atherosclerotic lesions, we found that CYP26B1 was the only member of the CYP26 family expressed, and it was highly inducible by atRA. Our data revealed that blocking CYP26B1 by chemical inhibition, or by targeted siRNA knock-down, resulted in significantly increased cellular retinoid levels. This indicates that CYP26B1 is an important modulator of endogenous retinoic acid levels. Therefore, we studied the effect of the CYP26B1 nonsynonymous polymorphism rs224105 on retinoic acid availability and found that the minor allele was associated with an enhanced retinoic acid catabolism rate and also with a slightly larger area of atherosclerotic lesions. The expression of CYP26B1 in human atherosclerotic lesions was localized to macrophage rich areas, suggesting retinoic acid activity in macrophages. Furthermore, we demonstrated that a CYP26B1 splice variant, that lack exon two, is expressed in vascular cells and in vessels walls. It is functional, with a reduced catabolic activity to around 70%, inducible by atRA in vascular cells and expressed 4.5 times more in atherosclerotic lesions compared to normal arteries. Moreover, the statins simvastatin and rosuvastatin reduced CYP26B1 mediated atRA catabolism in a concentration-dependent manner, and in vascular cells increased the mRNA expression of the atRA-responsive genes CYP26B1 and RARβ. This could lead to statins indirectly augmenting retinoic acid action in vascular cells which mimic statins roles. In conclusion, CYP26B1 is a major retinoic acid modulator in vascular cells and atherosclerotic lesions. Blocking of CYP26B1 could provide an advantageous therapeutic alternative to exogenous retinoid administration for treatment of vascular disorders.
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| 5. |
- Fransén, Karin, 1973-, et al.
(författare)
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Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8, s. e72739-
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Tidskriftsartikel (refereegranskat)abstract
- Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.
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| 7. |
- Kardeby, Caroline, 1989-, et al.
(författare)
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A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
- 2019
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 857
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Tidskriftsartikel (refereegranskat)abstract
- Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.
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| 9. |
- Nixon Tangi, Tebeng, et al.
(författare)
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Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells
- 2012
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Ingår i: International Journal of Molecular Medicine. - Athens, Greece : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 30:3, s. 697-702
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.
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| 10. |
- 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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