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A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
Örebro universitet, Hälsoakademin. (Department of Clinical Medicine)
Örebro universitet, Institutionen för hälsovetenskap och medicin. (Department of Clinical Medicine)
Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital Solna, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Vise andre og tillknytning
2012 (engelsk)Inngår i: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, nr 1, s. 712-718Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
New York, USA: The Feinstein Institute for Medical Research , 2012. Vol. 18, nr 1, s. 712-718
HSV kategori
Forskningsprogram
Medicin
Identifikatorer
URN: urn:nbn:se:oru:diva-23259DOI: 10.2119/molmed.2012.00094ISI: 000306034400018PubMedID: 22415012Scopus ID: 2-s2.0-84887594213OAI: oai:DiVA.org:oru-23259DiVA, id: diva2:530992
Forskningsfinansiär
Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)Wenner-Gren Foundations
Merknad

Funding Agencies:

Swedish Health Care Sciences Postgraduate School (NFVO) at Karolinska Institutet 

Bergwall's Foundation 

Tilgjengelig fra: 2012-06-05 Laget: 2012-06-05 Sist oppdatert: 2018-08-27bibliografisk kontrollert
Inngår i avhandling
1. CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
Åpne denne publikasjonen i ny fane eller vindu >>CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

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.

sted, utgiver, år, opplag, sider
Örebro: Örebro universitet, 2012. s. 62
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 71
Emneord
CYP26B1, alternative splice, vascular cells, atherosclerosis, alltrans-retinoic acid, gene polymorphism, inflammation, statins
HSV kategori
Forskningsprogram
Medicin
Identifikatorer
urn:nbn:se:oru:diva-22799 (URN)978-91-7668-877-9 (ISBN)
Disputas
2012-06-07, Hörsal HSP1, Prismahuset, Örebro universietet, Fakultetsgatan 1, Örebro, 13:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2012-05-10 Laget: 2012-05-10 Sist oppdatert: 2017-10-17bibliografisk kontrollert

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