Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6

Takeda, Norifumi; Manabe, Ichiro; Shindo, Takayuki; Iwata, Hiroshi; Iimuro, Satoshi; Kagechika, Hiroyuki; Shudo, Koichi; Nagai, Ryozo

doi:10.1161/01.atv.0000214296.94849.1c

Cited by 56 publications

(35 citation statements)

References 42 publications

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“…In line with this, low plasma retinol, the substrate for the active all-trans retinoic acid (atRA), is an independent risk factor for coronary events (10,11). Administration of retinoids also reduces post-balloon injury stenosis in rats (4,12,13) and ameliorates disease in atherosclerosis-prone mice (14).…”

Section: Introductionmentioning

confidence: 84%

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: Introductionmentioning

confidence: 84%

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Krivospitskaya

Elmabsout

Sundman

et al. 2012

Mol Med

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“…Based on these results, we initially speculated that Am80 might block RXR/PPAR␥ activation by HX630. However, Am80 has been suggested [62] to inhibit Cd36 tran-scription in macrophages via mechanisms that are independent of PPAR␥, because Am80 does not affect the reporter activity of PPAR␥ response element. The possibility remains that the Am80-RAR␣/␤ complex may outcompete PPAR␥ for RXR.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Kawahara

Suenobu

Ohtsuka

et al. 2014

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)␣,␤ agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-␤ protein precursor 23 (A␤PP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in A␤PP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A␤ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A␤ peptide in 8.5-month-old A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to A␤ clearance in Am80/HX630-treated A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric A␤ peptides by restoring impaired IL-4 signaling in A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

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“…In atherosclerotic rabbit models, atRA inhibited neointimal formation [8] and the outward remodeling of the vessel after balloon angioplasty [12]. Our previous studies suggest involvement of retinoids in the pathogenesis of atherosclerosis and restenosis [9,13], and recently Takeda et al [14] demonstrated that retinoids inhibit development of atherosclerosis in apolipoprotein-E-deficient mice.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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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Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6

Cited by 56 publications

References 42 publications

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

A CYP26B1 Polymorphism Enhances Retinoic Acid Catabolism and May Aggravate Atherosclerosis

Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

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

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