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CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2012. , p. 62
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 71
Keywords [en]
CYP26B1, alternative splice, vascular cells, atherosclerosis, alltrans-retinoic acid, gene polymorphism, inflammation, statins
National Category
Medical and Health Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-22799ISBN: 978-91-7668-877-9 (print)OAI: oai:DiVA.org:oru-22799DiVA, id: diva2:526059
Public defence
2012-06-07, Hörsal HSP1, Prismahuset, Örebro universietet, Fakultetsgatan 1, Örebro, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-05-10 Created: 2012-05-10 Last updated: 2017-10-17Bibliographically approved
List of papers
1. CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells
Open this publication in new window or tab >>CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells
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2011 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 48, no 1, p. 23-30Article in journal (Refereed) Published
Abstract [en]

Aim: The cytochrome P450 enzymes of the CYP26 family are involved in the catabolism of the biologically active retinoid all-trans-retinoic acid (atRA). Since it is possible that an increased local CYP26 activity would reduce the effects of retinoids in vascular injury, we investigated the role of CYP26 in the regulation of atRA levels in human aortic smooth muscle cells (AOSMCs).

Methods: The expression of CYP26 was investigated in cultured AOSMCs using real-time PCR. The metabolism of atRA was analyzed by high-performance liquid chromatography, and the inhibitor R115866 or small interfering RNA (siRNA) was used to suppress CYP26 activity/expression.

Results: AOSMCs expressed CYP26B1 constitutively and atRA exposure augmented CYP26B1 mRNA levels. Silencing of the CYP26B1 gene expression or reduction of CYP26B1 enzymatic activity by using siRNA or the inhibitor R115866, respectively, increased atRA-mediated signaling and resulted in decreased cell proliferation. The CYP26 inhibitor also induced expression of atRA-responsive genes. Therefore, atRA-induced CYP26 expression accelerated atRA inactivation in AOSMCs, giving rise to an atRA-CYP26 feedback loop. Inhibition of this loop with a CYP26 inhibitor increased retinoid signaling.

Conclusion: The results suggest that CYP26 inhibitors may be a therapeutic alternative to exogenous retinoid administration. Copyright (C) 2010 S. Karger AG, Basel

Place, publisher, year, edition, pages
S. Karger, 2011
Keywords
Retinoids, CYP26 enzyme family, Vascular smooth muscle cells, All-trans-retinoic acid catabolism, R115866 CYP26 inhibitor
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-22803 (URN)10.1159/000317397 (DOI)000283503700003 ()20606468 (PubMedID)
Available from: 2012-05-11 Created: 2012-05-10 Last updated: 2018-09-05Bibliographically approved
2. A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
Open this publication in new window or tab >>A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis
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2012 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 18, no 1, p. 712-718Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
New York, USA: The Feinstein Institute for Medical Research, 2012
National Category
Medical and Health Sciences Biochemistry and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-23259 (URN)10.2119/molmed.2012.00094 (DOI)000306034400018 ()22415012 (PubMedID)2-s2.0-84887594213 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)Wenner-Gren Foundations
Note

Funding Agencies:

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

Bergwall's Foundation 

Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2018-08-27Bibliographically approved
3. Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells
Open this publication in new window or tab >>Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, article id e36839Article in journal (Refereed) Published
Abstract [en]

Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the fulllength enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

Place, publisher, year, edition, pages
San Francisco, USA: Public Library Science, 2012
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-23025 (URN)10.1371/journal.pone.0036839 (DOI)000305349600006 ()22666329 (PubMedID)2-s2.0-84861551190 (Scopus ID)
Funder
Swedish Research Council
Note

Funding Agencies:

Örebro University 

Available from: 2012-05-31 Created: 2012-05-30 Last updated: 2019-03-26Bibliographically approved
4. Simvastatin and rosuvastatin inhibit CYP26B1-mediated retinoid catabolism
Open this publication in new window or tab >>Simvastatin and rosuvastatin inhibit CYP26B1-mediated retinoid catabolism
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-23257 (URN)
Available from: 2012-06-05 Created: 2012-06-05 Last updated: 2017-10-17Bibliographically approved

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Elmabsout, Ali Ateia

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