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Retinoid metabolism and signalling in vascular smooth muscle cells
Örebro University, Department of Clinical Medicine.
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 [en]
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: urn:nbn:se:oru:diva-1306ISBN: 978-91-7668-541-9 (print)OAI: oai:DiVA.org:oru-1306DiVA, id: diva2:134887
Public defence
2007-06-01, Hörsal P2, Prismahuset, Fakultetsgatan 1, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2007-05-11 Created: 2007-05-10 Last updated: 2017-10-18Bibliographically approved
List of papers
1. Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells
Open this publication in new window or tab >>Differences in retinol metabolism and proliferative response between neointimal and medial smooth muscle cells
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2006 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 392-398Article in journal (Refereed) Published
Abstract [en]

Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol dehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.

National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-2840 (URN)10.1159/000094415 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
2. CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells
Open this publication in new window or tab >>CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells
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2007 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 27, no 7, p. 1542-1548Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26). Thus, an alternative approach to exogenous retinoid administration could be to increase the intracellular level of all-trans retinoic acid by blocking CYP26-mediated degradation of retinoids.

METHODS AND RESULTS: Vascular intimal and medial SMCs expressed CYP26A1 and B1 mRNA. Although medial cells remained unaffected, treatment with the CYP26-inhibitor R115866 significantly increased cellular levels of all-trans retinoic acid in intimal SMCs. The increased levels of all-trans retinoic acid induced retinoid-regulated genes and decreased mitogenesis.

CONCLUSIONS: Blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. Therefore, CYP26-inhibitors offer a potential new therapeutic approach to vascular proliferative disorders.

Place, publisher, year, edition, pages
Baltimore, Md: Lippincott Williams & Wilkins, 2007
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-2841 (URN)10.1161/ATVBAHA.106.138602 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
3. The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cells
Open this publication in new window or tab >>The importance of CYP26 in the regulation of atRA metabolism in human atherosclerotic lesions and aortic smooth muscle cells
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(English)Manuscript (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-2842 (URN)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-10-18Bibliographically approved
4. Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid
Open this publication in new window or tab >>Expression of IL-1β, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid
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2006 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 377-382Article in journal (Refereed) Published
Abstract [en]

The proinflammatory cytokine interleukin (IL)-1β and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1β levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1β protein. atRA-treated carotid lesions showed significantly elevated IL-1β mRNA levels (2.9 ± 2.33) compared with untreated lesions (2.0 ± 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.

National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-2843 (URN)10.1159/000094258 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved

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