Published online before print May 17, 2007, doi: 10.1161/ATVBAHA.106.138602
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© 2007 American Heart Association, Inc.
Vascular Biology |
CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells
From the Division of Biomedicine, Department of Clinical Medicine (P.O., A.S.), University of Örebro; the Center for Molecular Medicine, Experimental Cardiovascular Research Unit (A.C.G., P.S.O.), Karolinska Institute, Stockholm; and the Department of Medical Sciences/Dermatology (H.T.), Uppsala University, Sweden.
Correspondence to Andreas C. Gidlöf, Center for Molecular Medicine, L8:03, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail andreas.gidlof{at}cmm.ki.se Author to receive reprint requests: Pauline Ocaya, Division of Biomedicine, Department of clinical medicine, University of Örebro, 701 82 Örebro, Sweden.
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Abstract |
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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-inibitors offer a potential new therapeutic approach to vascular proliferative disorders.
atRA regulates proliferation and differentiation of various cell types. We show that inhibition of CYP26 by R115866 in intimal SMCs results in increased cellular retinoids and retinoidal effects, ie, inhibition of DNA synthesis and alteration of cell morphology. Therefore, CYP26 inibitors offer a potential new therapeutic approach to vascular proliferative disorders.
Key Words: retinoids • CYP26 • retinoid metabolism • vascular smooth muscle cells
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Introduction |
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Smooth muscle cells (SMCs) play a key role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis1 and postangioplasty restenosis.2 Intimal SMCs are dedifferentiated SMCs with a powerful capacity to proliferate and migrate, features that were mostly studied in intimal hyperplasia after vascular interventions. These cells are epitheloid-shaped in vitro and, thus, morphologically distinguishable from SMCs of the media that are spindle-shaped.3 Epithelioid-shaped SMCs play an important role in cardiovascular diseases, including atherosclerosis,4,5 restenosis,6 and hypertension.7 Retinoids have been demonstrated to prevent atherogenesis,8 inhibit intimal hyperplasia,6,9 and have been implicated in vascular remodeling in pulmonary hypertension patients.10 Retinoids inhibit intimal hyperplasia after vascular injury6,9 by reducing SMC proliferation.11 They are known to influence differentiation of various cell types, and previous studies indicate that retinoids can alter the phenotype of vascular SMCs.9,12 To date, a number of genes have been identified as markers of intimal SMCs including tropomyosin 4,13 cytokeratins,14 and cellular retinol binding protein-1 (CRBP-1).15 Interestingly, CRBP-1 is involved in retinoid metabolism,16 suggesting an altered retinoid metabolism in the intima. Indeed, we previously demonstrated that intimal SMCs have higher capacity to metabolize retinol into the active metabolite, all-trans retinoic acid (atRA), than medial SMCs.17 The inhibition of DNA synthesis in intimal SMCs, in contrast to increased DNA synthesis in medial SMCs on retinol stimulation,17 further supports the concept of differential retinoid metabolism in these subsets of cells.
The metabolism of retinoids is complex and involves multiple binding proteins and metabolizing enzymes. The synthesis of retinoic acid (RA) is a 2-step reaction involving substrate-specific enzymes and cellular retinol binding proteins. The first step is the reversible oxidation of retinol (ROH) into retinal by retinol dehydrogenases (RDH).16,18 The second step, the oxidation of retinal into the biologically active RA, is carried out by retinal dehydrogenases (RalDH). RA activates 2 families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are ligand-inducible transcription factors. Retinoids exert their effects on gene transcription mainly through 2 active stereoisomers, atRA and 9-cis retinoic acid (9-cisRA).19
Intracellular levels of active retinoids are under strict control. RA catabolism is carried out by cytochrome p450 isoform 26, CYP26, a regulator of intracellular retinoid levels that specifically metabolizes retinoic acid into secretable polar metabolites, eg, 4-oxo RA and 18- OH-RA.16,20 Three isoforms are known: CYP26A1, CYP26B1, and CYP26C1.21–27 CYP26 is regulated by all-trans RA through RA-induced transactivation of retinoic acid responsive elements located in the CYP26 promoters,28,29 suggesting a role for CYP26 as a damper of the cellular levels of RA. Indeed, CYP26 knockout mice have a lethal morphogenetic phenotype mimicking that observed after administration of excess atRA.30 Furthermore, oral treatment of rats with the same CYP26 inhibitor as we have used in the present study, R115866, increases both plasma and tissue levels of atRA and generates retinoidal effects.31 Studies showing the importance of CYP26 in the regulation of retinoid levels in vascular SMCs are lacking. Because intimal SMCs have a high capacity to produce the biologically active atRA, we hypothesized that the blocking of CYP26-mediated atRA-metabolism by R115866 would increase the endogenous levels of retinoids and mimic the effects of exogenous retinoids on intimal SMCs. We therefore performed this study to explore the importance of CYP26 in the regulation of retinoid levels in vascular SMCs.
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Methods |
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For details on methods, please see the supplemental materials (available online at http://atvb.ahajournals.org).
Chemicals
All-trans Retinol (atROH) and atRA, obtained from Sigma Aldrich, were dissolved and diluted in dimethyl sulfoxide (DMSO) and handled in a light-restricted regime. [3H]-atROH and [3H]-atRA were purchased from PerkinElmer Life and Analytical Sciences. [methyl-3H]Thymidine was purchased from Amersham Biosciences Europe GMBH. The pan-RAR antagonist CD3106 was a generous gift from Galderma R&D (Sophia-Antipolis, France). The CYP26 inhibitor R115866 was generously supplied by Dr Jean Van Wauwe (Janssen Pharmaceutica, Beerse, Belgium).
Cell Isolation and Culture
SMCs were isolated from the neointima of the rat aorta 2 weeks after balloon angioplasty (hereafter referred to as intimal SMCs) or from medial layer of the thoracic aorta of 6-week-old male Sprague-Dawley rats (ALAB, Sollentuna, Sweden) (referred to as medial SMCs).32
Retinoid Uptake and Metabolism in Intimal SMCs
The uptake and metabolism of [3H]atROH and [3H]atRA was studied in medial and intimal SMCs cultured in DMEM/F12 with 10% FCS. Cells were preincubated with R115866 (1 µmol/L) or vehicle (DMSO) for 4 hours before retinoid incubation. Cell-associated radioactivity was separated by high-performance liquid chromatography (HPLC) and normalized to the amount of protein extract.
Real-Time Polymerase Chain Reaction
Cells were exposed to different concentrations of atRA, atROH, CD3106, R115866, or vehicle (DMSO), and the mRNA levels of CYP26A1, CYP26B1, RAR-ß, and hypoxanthine guanine phosphoribosyl transferase were determined by real-time polymerase chain reaction (PCR).
Measurement of DNA Synthesis
Cultured cells were exposed to atRA or atROH in the presence or absence of R115866 for different periods, and then incubated with 3H-thymidine (1.0 µCi/mL medium) 24 hours before harvest. Radioactivity was measured in a liquid scintillation counter.
Image Acquisition
The effects of atRA and R115866 on intimal SMCs were studied using a microscope.
Statistical Analysis
Comparisons between 2 groups were analyzed using Student t test. Multiple comparisons were made using 1-way analysis of variance (ANOVA) with Bonferroni adjustment. P<0.05 was considered statistically significant. Values are presented as mean±SEM.
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Expression and Regulation of CYP26 in Intimal SMCs
Treatment of intimal SMCs cells with atRA doses ranging from 10 to 100 nmol/L for 6 hours showed that a stimulus of cells with 100 nmol/L significantly increases the expression of both CYP26B1 and A1 (Figure 1A and 1B). The expression of CYP26B1 and CYP26A1 mRNA was also significantly increased in intimal SMCs after treatment with atRA (1µmol/L) for 6 to 72 hours (Figure 1C and 1D). These inductions peaking at 6 hours after atRA treatment were significant through out the incubation period for CYP26 B1, and up to 48 hours for CYP26A1 (Figure 1C and 1D). To compare CYP26 expression in intimal SMCs and medial SMCs, medial SMCs were treated with 1µmol/L atRA for 6 to 72 hours. The expression of CYP26A1 and CYP26B1 mRNA in medial SMCs was also significantly induced by atRA (Figure 1E and 1F).
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Effects of CYP26 Inhibition on Retinoid Uptake and Metabolism
We proceeded to investigate the impact of CYP26 inhibition on the metabolism of exogenously administered [3H]-atRA and [3H]-atROH in intimal SMCs using HPLC. Incubation of intimal SMCs with the R115866 before atRA exposure resulted in 10 to 20 times increased cellular levels of [3H]-atRA (Table). Incubation of cells with R115866 before [3H]-atROH exposure also caused a 2 to 4 times increase in the cellular levels of [3H]-atROH (Table). The cellular level of synthesized atRA from [3H]-atROH was 4-fold higher in cells that were incubated with R115866 before [3H]-atROH exposure. The cellular level of [3H]-atRA was also significantly increased when medial SMCs were incubated with R115866 before atRA exposure; however, the levels of synthesized atRA after [3H]-atROH exposure was not affected by the CYP26 inhibitor (supplemental Table I).
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Effects of CYP26 Inhibition on Expression of atRA Regulated Genes
To study the effects of CYP26 inhibition on the expression of atRA-regulated genes, we investigated the levels of atRA responsive genes CYP26A1,24 CYP26B1,33 and RAR-ß.34 Intimal SMCs were exposed to atROH in the presence or absence of R115866 for 24 or 48 hour. R115866 alone induced a significant increase in CYP26B1 and RAR-ß mRNA expression (Figure 2A and 2C). However, both R115866 and atROH were necessary for the induction of CYP26A1 (Figure 2B).
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Effects of CYP26 Inhibition on DNA Synthesis
Intimal SMCs were exposed to 1 µmol/L R115866, 0.05 µmol/L atRA, 5 µmol/L atROH, or a combination of R115866 and retinoid for 1 to 5 days, which resulted in a significant reduction of DNA synthesis compared with the DMSO-treated controls at day 1 and 2 (Figure 3A). Addition of R115866 to individual treatments (atRA or atROH) further enhanced inhibition of DNA synthesis (Figure 3A). At days 3 to 5, addition of R115866 to atRA- or atROH-treated cells was required for inhibition of the DNA synthesis (Figure 3A).
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In agreement with previous study,9 atRA alone significantly reduced DNA synthesis in intimal SMCs in a dose-dependent manner (Figure 3B). Interestingly, addition of R115866 to atRA-stimulated cells increased atRA-sensitivity (Figure 3B). DNA synthesis in medial SMCs was also significantly inhibited dose-dependently by atRA (Figure 3C). R115866 potently enhanced atRA-effects on DNA synthesis only at lowest atRA concentration (0.005µmol/L) in medial SMCs (Figure 3C).
To investigate whether the retinoid and R115866 effects on DNA synthesis in intimal SMCs were RAR-mediated, we coincubated the cells with CD3106. As shown in Figure 3C, the effects of individual (5 µmol/L atROH, 0.05 µmol/L atRA, 1 µmol/L R115868) and combinatory treatments (atROH + R115866 or atRA + R115866) were then partially inhibited by 0.5 µmol/L CD3106.
To investigate whether the basal expression of CYP26 in intimal SMCs was regulated by constitutive production of RAR ligands, we incubated cells with the pan-RAR antagonist CD3106 for 6 to 48 hours. CD3106 significantly inhibited the expression of CYP26B1 at 24 hours of incubation and resulted in a tendency toward lower levels of CYP26A1 mRNA (supplemental Figure IA and IB).
Morphological Effects of CYP26 Inhibition on Intimal SMCs
Exposure of intimal SMCs to 1 µmol/L atRA or 1 µmol/L R115866 for 72 hours resulted in marked morphological changes as compared with control (supplemental Figure II). Intimal SMCs in the control group were epithelioid-shaped (supplemental Figure IIA and IIB). Morphological alterations to a more spindle-shaped type were observed after addition of atRA (Figure IIC and IID) and R115866 (Figure IIE and IIF). However, Western blotting analysis revealed no changes in the protein levels of the SMC differentiation marker smooth muscle myosin heavy chain after atRA or R115866 exposure (data not shown).
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Discussion |
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In this study, we demonstrate that intimal SMCs express mRNA encoding the retinoid catabolizing enzymes CYP26A1 and CYP26B1, and inhibition of CYP26 by the synthetic R115866 significantly increase cellular retinoid levels. The resulting increased availability of cellular atRA augmented expression of several retinoid-regulated genes, reduced mitogenesis and a shift of the intimal SMC phenotype toward the spindle-shaped morphology. CYP26A1 and CYP26B1 mRNA was also expressed by medial SMCs. Blockage of CYP26 in medial SMCs, however, did not inhibit the catabolism of newly synthesized atRA, suggesting that CYP26 alone is not an important regulator of endogenous retinoid levels in medial SMCs. Both CYP26 isoforms were rapidly induced after atRA treatment in intimal and medial SMCs, indicating that vascular SMCs respond promptly to excess atRA. The importance of a tightly regulated intracellular retinoid metabolism for normal embryonal development is well established.35 Thus, our finding of a retinoid-regulated expression of CYP26 in intimal and medial SMCs may have several implications on vascular biology, including a potential treatment of certain proliferative disorders. The importance of phenotypically-modulated SMCs with powerful migratory and proliferatory abilities has been demonstrated in atherosclerosis36 and restenosis37 where they are involved in intimal thickening. This makes intimal SMCs an important therapeutic target.
The capability of atRA-mediated CYP26 induction in intimal SMCs indicates an increased capacity to inactivate intracellular retinoids by degradation.20,22,23 As an effect of the decrease in the intracellular catabolism of these compounds, the cellular concentrations of both atRA and its prohormone, atROH, were significantly increased when the intimal SMCs were pretreated with R115866. Our findings suggest that inhibition of CYP26 in intimal SMCs not only strongly impedes degradation of atRA, but also to some extent of atROH, which supports previous reports of CYP26 affinity for atROH.38,39 Hence, CYP26 inhibition results not only in less atRA degradation, but also in more cellular substrate for atRA synthesis. Interestingly, atRA induces Stimulated by Retinoic Acid 6, which increases the RBP mediated uptake of ROH.40 This ROH could subsequently be used by the cell either for atRA synthesis or storage in retinyl esters. Furthermore, as we previously demonstrated,17 we show that vascular SMCs are able to metabolize atROH into atRA. We also demonstrate that presence of R115866 results in a significant increase of the cellular concentrations of synthesized atRA in intimal SMCs. To evaluate the biological importance of CYP26 inhibition in intimal SMCs, we studied the expression of the known atRA regulated genes CYP26A1, CYP26B1, and RAR-ß34,41 after R115866 treatment. R115866 caused a significant increase in the expression of CYP26B1 and RAR-ß, which demonstrates that inhibition of CYP26-mediated retinoid catabolism causes a biologically significant increase of active retinoid signaling. Moreover, the basal expression of CYP26B1 in intimal SMCs was decreased after treatment with the pan-RAR antagonist CD3106, demonstrating that its regulation involves RARs. Both RAR-ß and CYP26A1 are known to contain a retinoid responsive elements (RARE) in their promoter.28,34 Although no RARE has yet been identified in the CYP26B1 promoter, multiple RA-responsive genes have been reported that do not contain RARE in their promoter region.41 Rat smooth muscle cells express mainly RAR-
,42 suggesting that the effects of CYP26 inhibition seen in this study may be mediated through this receptor.
We furthermore demonstrate that the inhibition of CYP26 and thus increased intracellular levels of atRA results in morphological modulation of the epitheliod shaped intimal SMCs to a more spindle shaped SMCs, an effect observed after atRA stimulation in previous studies.15 Interestingly, treatment with atRA and R115866 did not induce the expression of the smooth muscle differentiation marker smooth muscle myosin heavy chain in intimal SMCs. We previously showed that atRA decreases the expression of smooth muscle -actin in intimal SMCs.9 In contrast, other investigators found that atRA increases the expression of both smooth muscle -actin and smooth muscle myosin heavy chain43,44 in SMCs from the medial layer of the vessel. This suggests that the differentiation state of the SMC influences the effects of atRA on the expression of contractile proteins.
The findings demonstrate that blocking of the CYP26-related retinoid catabolism by R115866 may both enhance and prolong the effects of atRA on intimal and medial SMC growth. Also, R115866 alone inhibited DNA synthesis in intimal SMCs, an effect that partly was blocked by the RAR antagonist CD3106, indicating that the effects of R115866 on cell proliferation may be mediated through increased cellular levels of RAR ligands.
To date, exogenous retinoids have been used to treat a multitude of hyperproliferative disorders ranging from leukemia45 to psoriasis.46 Also in SMCs, the antimitogenic effects are well established both in vitro and in vivo, and atRA has been shown to decrease intimal hyperplasia after vascular interventions in animal models.6,9,47 It is, therefore, conceivable that modulation of vascular atRA levels potentially would have beneficial effects on the exaggerated SMC proliferation seen in common vascular disorders as poststent restenosis. The long-term clinical use of exogenous retinoids is, however, limited because of development of tolerance.48,49 As suggested in several studies, CYP26 most likely plays a role in this acquired retinoid resistance.50,51 Indeed, the lack of effects on DNA synthesis after 4 days of treatment with atROH or low levels of atRA seen in this study, which may be overcome by combinatory treatment with R115866, suggests that CYP26 contributes to the development of atRA tolerance in intimal SMCs. Thus we speculate that, if retinoids prove as efficient in human restenosis as in the various animal models,6,9,47 inhibitors of CYP26 could be a suitable mean to achieve increased local atRA levels at vascular sites of disease.
In summary, the CYP26-inhibitor R115866 offers a new approach to increase the intracellular concentration of biologically active retinoids, ie, blocking of the CYP26-mediated catabolism of atRA, which results in significant biological effects on gene expression, cellular proliferation, and cell morphology. We, therefore, conclude that blocking of the CYP26-mediated catabolism mimics the effects of exogenously administrated active retinoids on intimal SMCs. CYP26-inhibitors potentially offer a new therapeutic approach to vascular proliferative disorders.
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Acknowledgments |
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Sources of Funding
The study was supported by grants from the Swedish Medical Research Council (K2002-71X-02042-36A), the Swedish Heart Lung Foundation, and Laerdahl Foundation.1
Disclosures
Hans Törmä, is presently involved in a Phase-I study sponsored by Barrier therapeutics (supplier of R115866 in this study).
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Footnotes |
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A.C.G. and P.O. contributed equally to this study.
Original received December 19, 2006; final version accepted April 16, 2007.
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