CYP26B1 Plays a Major Role in the Regulation of All-&lt;i&gt;trans&lt;/i&gt;-Retinoic Acid Metabolism and Signaling in Human Aortic Smooth Muscle Cells

Ocaya, Pauline; Elmabsout, Ali Ateia; Olofsson, Peder S.; Törmä, Hans; Gidlöf, Anders; Sirsjö, Allan

doi:10.1159/000317397

Cited by 23 publications

(30 citation statements)

References 51 publications

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“…We and others previously showed that pharmacological inhibition of CYP26, or RNA interference (RNAi)-mediated CYP26 silencing, increases levels of retinoic acid and retinoid signaling (27,28,42). Hence, because our data indicate that the CYP26B1 enzyme was present and upregulated in atherosclerosis, regulation of CYP26B1 activity may influence atherosclerosis development by altering the local availability of retinoid ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Semiquantitative polymerase chain reaction (PCR) was performed in a 7900HT Fast Real-Time PCR System using Assays-on-Demand™ reagents (Applied Biosystems, Foster City, CA, USA) for human CYP26B1. β-Actin was used as a reference (28). Formalin fixed 10-μm cryosections or arterial biopsies were incubated with mouse anti-CYP26B1 (Abnova, Thaipei City, Taiwan), anti-CD68 or anti-α-actin (Dakopatts, Glostrup, Denmark) monoclonal antibodies or a relevant isotype control overnight at 4°C after treatment with 0.3% H 2 O 2 (Sigma-Aldrich).…”

Section: Human Biopsiesmentioning

confidence: 99%

“…CYP26B1 has 41% amino acid identity with CYP26A1 but similar functional activity (24,25). In subsets of vascular and immune cells, interference with CYP26 has profound effects on atRA levels (26)(27)(28), and increased levels of endogenous atRA result in induction of a number of retinoid-responsive genes in vascular cells (27). To date, little is known about the significance of genetic polymorphisms that occur in the CYP26 enzymes.…”

Section: Introductionmentioning

confidence: 99%

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A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Human Biopsiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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“…With increased levels of endogenous atRA, a number of retinoid responsive genes are induced, suggesting that CYP26B1 may be a key enzyme in the regulation of retinoid levels in the vessel wall (25). CYP26B1 was shown to be the major CYP26 expressed and induced by atRA and it is believed to be an important regulator of atRA levels in human vascular cells [24], [25]. We have recently found increased levels of CYP26B1 in atherosclerotic lesions, with the strongest expression found in macrophage-rich, inflammatory areas of the lesions [4].…”

Section: Introductionmentioning

confidence: 94%

Cloning and Functional Studies of a Splice Variant of CYP26B1 Expressed in Vascular Cells

et al. 2012

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BackgroundAll-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.Methodology/Principal FindingsThe coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.Conclusions/SignificanceVascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

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“…Although the CYP26B1 splice variant lacks exon 2 in the coding region, it still has the ability to downgrade at-RA [39]. A previous study indicated that full-length CYP26B1 plays a crucial role in the catabolism of at-RA and regulation signaling [40], whereas the splice variant of CYP26B1 exerts slight or no influence on at-RA regulation [39]. …”

Section: Discussionmentioning

confidence: 99%

Expression of a Splice Variant of CYP26B1 in Betel Quid-Related Oral Cancer

Chen

Lee

Hsu

et al. 2014

The Scientific World Journal

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Betel quid (BQ) is a psychostimulant, an addictive substance, and a group 1 carcinogen that exhibits the potential to induce adverse health effects. Approximately, 600 million users chew a variety of BQ. Areca nut (AN) is a necessary ingredient in BQ products. Arecoline is the primary alkaloid in the AN and can be metabolized through the cytochrome P450 (CYP) superfamily by inducing reactive oxygen species (ROS) production. Full-length CYP26B1 is related to the development of oral pharyngeal cancers. We investigated whether a splice variant of CYP26B1 is associated with the occurrence of ROS related oral and pharyngeal cancer. Cytotoxicity assays were used to measure the effects of arecoline on cell viability in a dose-dependent manner. In vitro and in vivo studies were conducted to evaluate the expression of the CYP26B1 splice variant. The CYP26B1 splice variant exhibited lower expression than did full-length CYP26B1 in the human gingival fibroblast-1 and Ca9-22 cell models. Increased expression of the CYP26B1 splice variant was observed in human oral cancer tissue compared with adjacent normal tissue, and increased expression was observed in patients at a late tumor stage. Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer.

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CYP26B1 Plays a Major Role in the Regulation of All-<i>trans</i>-Retinoic Acid Metabolism and Signaling in Human Aortic Smooth Muscle Cells

Cited by 23 publications

References 51 publications

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Cloning and Functional Studies of a Splice Variant of CYP26B1 Expressed in Vascular Cells

Expression of a Splice Variant of CYP26B1 in Betel Quid-Related Oral Cancer

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