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The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cells
Örebro University, Department of Clinical Medicine.
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(English)Manuscript (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-2842OAI: oai:DiVA.org:oru-2842DiVA, id: diva2:134885
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-10-18Bibliographically approved
In thesis
1. Retinoid metabolism and signalling in vascular smooth muscle cells
Open this publication in new window or tab >>Retinoid metabolism and signalling in vascular smooth muscle cells
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Smooth muscle cells (SMCs) play a major role in cardiovascular diseases. In advanced atherosclerosis, blood flow is impaired due to reduced luminal diameter. Percutaneous vascular interventions, including balloon angioplasty and stent-application are commonly used for the re-establishment of luminal size and improvement of tissue perfusion. However, the benefit of vascular interventions is hampered by re-stenosis. The molecular basis of re-stenosis is not fully elucidated and so far, no successful treatment is clinically available. Re-stenosis, which is proposed to be a response to mechanical injury, involves the activation of multiple processes including inflammation, SMC migration and proliferation, and is characterized by vessel remodelling and intimal hyperplasia.

Retinoids have been shown to regulate several processes activated at site of vascular injury including inflammation, SMC migration and proliferation, and have been demonstrated to inhibit SMC proliferation and reduce intimal hyperplasia. Thus, retinoids are potential candidates in the treatment of certain vascular disorders. Retinoid metabolism is complex and involves a repertoire of proteins including retinoic acid synthesizing and catabolizing enzymes. The purpose of this study was to investigate retinoid metabolism in vascular cells, more specifically to find key points in the regulation of retinoid metabolism in vascular SMCs and atherosclerotic lesions.

We demonstrate that different phenotypes of SMCs exhibit differences in retinoid metabolism, which suggests a link between retinoid metabolism and the SMC phenotype. Vascular SMCs and atherosclerotic lesions expressed cytochrome P450 isoform 26 (CYP26) enzymes, which are involved in retinoid catabolism. Our studies reveal the presence of a negative feedback loop, in which retinoids induce its inactivation by inducing CYP26 expression in vascular SMCs and atherosclerotic lesions. Moreover, inhibition of CYP26 potently blocked retinoid catabolism and resulted in retinoid-like effects in SMCs, indicating that CYP26 is an important endogenous modulator of retinoid metabolism in vascular cells. In atherosclerotic lesions and vascular SMCs, decreased retinoid catabolism and hence, increased retinoid availability, resulted in increased expression of retinoid-responsive genes.

Since retinoids reduce intimal hyperplasia in animal models, our studies suggest that CYP26 inhibitors may provide an alternative to exogenous retinoid administration. Thus, CYP26 inhibitors may offer a new therapeutic approach to vascular proliferative disorders.

Place, publisher, year, edition, pages
Örebro: Örebro universitetsbibliotek, 2007. p. 55
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 11
Keywords
all-trans Retinol, all-trans Retinoic acid, retinoid metabolism, proliferation, Vascular smooth muscle cells, CYP26
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-1306 (URN)978-91-7668-541-9 (ISBN)
Public defence
2007-06-01, Hörsal P2, Prismahuset, Fakultetsgatan 1, Örebro, 10:00 (English)
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Supervisors
Available from: 2007-05-11 Created: 2007-05-10 Last updated: 2017-10-18Bibliographically approved

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Ocaya, Pauline A.Sirsjö, Allan

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CiteExportLink to record
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Citation style
  • apa
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