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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

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          Abstract

          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.

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          Most cited references18

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          CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family.

          A novel member of the cytochrome P450 superfamily, CYP26, which represents a new family of cytochrome P450 enzymes, has been cloned. CYP26 mRNA is up-regulated during the retinoic acid (RA)-induced neural differentiation of mouse embryonic stem cells in vitro and is transiently expressed by embryonic stem cells undergoing predominantly non-neural differentiation. CYP26 transcript is detectable as early as embryonic day 8.5 in mouse embryos, suggesting a function for the gene in early development. CYP26 is expressed in mouse and human liver, as expected for a cytochrome P450, and is also expressed in regions of the brain and the placenta. Acute administration of 100 mg/kg all-trans-RA increases steady-state levels of transcript in the adult liver, but not in the brain. CYP26 is highly homologous to a Zebrafish gene, CYPRA1, which has been proposed to participate in the degradation of RA, but is minimally homologous to other mammalian cytochrome P450 proteins. Thus, we report the cloning of a member of a novel cytochrome P450 family that is expressed in mammalian embryos and in brain and is induced by RA in the liver.
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            Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism.

            Retinoids, particularly all-trans-retinoic acid (RA), are potent regulators of cell differentiation, cell proliferation, and apoptosis. The role of all-trans-RA during development and in the maintenance of adult tissues has been well established. The control of all-trans-RA levels in cells and tissues is regulated by the balance between its biosynthesis and its catabolism to inactive metabolites. The cytochrome P450 enzyme P450RAI (herein renamed P450RAI-1) is partially responsible for this inactivation of all-trans-RA. In this report, we describe the identification, molecular cloning, and characterization of a second related enzyme, P450RAI-2, which is also involved in the specific inactivation of all-trans-RA. Transiently transfected P450RAI-2 can convert all-trans-RA to more polar metabolites including 4-oxo-, 4-OH-, and 18-OH-all-trans-RA. Competition experiments with other retinoids suggest that all-trans-RA is the preferred substrate. The high level of expression of P450RAI-2, particularly in the cerebellum and pons of human adult brain, suggests a unique role for this enzyme in the protection of specific tissues from exposure to retinoids.
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              Retinoic acid regulates endothelial cell proliferation during vasculogenesis.

              A dietary deficiency of vitamin A is associated with cardiovascular abnormalities in avian and murine systems. Retinoic acid (RA) is the active metabolite of vitamin A and whether it directly regulates mammalian blood vessel formation has not been determined and is investigated herein. We used mice rendered RA-deficient via targeted deletion of retinaldehyde dehydrogenase 2 (Raldh2(-/-)), the enzyme required to produce active RA in the embryo. Histological examination at E8.0-8.5, prior to cardiac function and systemic blood circulation, revealed that capillary plexi formed in Raldh2(-/-) yolk sacs and embryos, but were dilated, and not appropriately remodeled or patterned. Raldh2(-/-) endothelial cells exhibited significantly increased expression of phosphohistone 3 and decreased expression of p21 and p27, suggesting that RA is required to control endothelial cell cycle progression during early vascular development. Uncontrolled endothelial cell growth, in Raldh2(-/-) mutants, was associated with decreased endothelial cell maturation, disrupted vascular plexus remodeling and lack of later stages of vessel assembly, including mural cell differentiation. Maternally administrated RA restored endothelial cell cycle control and vascular patterning. Thus, these data indicate that RA plays a crucial role in mammalian vascular development; it is required to control endothelial cell proliferation and vascular remodeling during vasculogenesis.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2011
                December 2010
                06 July 2010
                : 48
                : 1
                : 23-30
                Affiliations
                aDivision of Biomedicine, Department of Clinical Medicine, Örebro University, Örebro, bCenter for Molecular Medicine, Department of Anesthesiology and Intensive Care Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, and cDepartment of Medical Sciences/Dermatology, Uppsala University, Uppsala, Sweden; dDepartment of Cell and Developmental Biology, Weill Medical College of Cornell University, and eLaboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, N.Y., USA
                Article
                317397 J Vasc Res 2011;48:23–30
                10.1159/000317397
                20606468
                3b73a2b2-6ecc-4390-835d-fa1767db7b81
                © 2010 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 17 December 2009
                : 30 January 2010
                Page count
                Figures: 5, References: 34, Pages: 8
                Categories
                Research Paper

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Retinoids,CYP26 enzyme family,Vascular smooth muscle cells,R115866 CYP26 inhibitor,All-trans-retinoic acid catabolism

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