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CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells
Örebro University, School of Health and Medical Sciences. (Cardiovascular research unit)
Örebro University, School of Health and Medical Sciences.
Dept Anesthesiol & Intens Care Med, Ctr Mol Med, Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden .
Dept Med Sci Dermatol, Uppsala Univ, Uppsala, Sweden.
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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. Vol. 48, no 1, p. 23-30
Keywords [en]
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: urn:nbn:se:oru:diva-22803DOI: 10.1159/000317397ISI: 000283503700003PubMedID: 20606468OAI: oai:DiVA.org:oru-22803DiVA, id: diva2:526079
Available from: 2012-05-11 Created: 2012-05-10 Last updated: 2018-09-05Bibliographically approved
In thesis
1. CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
Open this publication in new window or tab >>CYP26B1 as regulator of retinoic acid in vascular cells and atherosclerotic lesions
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
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:nbn:se:oru:diva-22799 (URN)978-91-7668-877-9 (ISBN)
Public defence
2012-06-07, Hörsal HSP1, Prismahuset, Örebro universietet, Fakultetsgatan 1, Örebro, 13:15 (Swedish)
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Available from: 2012-05-10 Created: 2012-05-10 Last updated: 2017-10-17Bibliographically approved

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Ocaya, Pauline AjokElmabsout, Ali AteiaSirsjö, Allan

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