Dataset Information

Adenosine A2a Receptor Blockade Diminishes Wnt/?-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

ABSTRACT: Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/?-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/?-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/?-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of ?-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated ?-catenin or ?-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated ?-catenin and ?-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/?-catenin signaling pathway, contributing to its capacity to inhibit dermal fibrosis in diseases such as scleroderma.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5809334 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Adenosine A2a Receptor Blockade Diminishes Wnt/β-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

Zhang Jin J Corciulo Carmen C Liu Hailing H Wilder Tuere T Ito Mayumi M Cronstein Bruce B

The American journal of pathology 20170628 9

Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/β-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/β-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/β-catenin signaling was involved in diffuse derm ...[more]

PMID: 28667836

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Project description:BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. So far, no Western medicine treatment can completely inhibit or reverse the progress of SSc, while at the same time, our previous series of studies have shown that the treatment of SSc by the Wenyang Huazhuo Tongluo formula (WYHZTL), a Chinese herbal decoction, shows a delightful prospect. The aim of this study is to further investigate the mechanism of anti-fibrosis of WYHZTL formula in SSc mouse model.MethodsThe Bleomycin-induced SSc mouse model was treated with saline (BLM), high-dosage of WYHZTL formula (WYHZTL-H), medium-dosage of WYHZTL formula (WYHZTL-M), low-dosage of WYHZTL formula (WYHZTL-L) and XAV-939, a small molecule inhibitor of Wnt/β-catenin signaling pathway, by the intragastric administration and intraperitoneal injection, respectively. The mRNA and protein levels of Wnt/β-catenin signaling pathway associated genes, fibrosis markers and histopathology were detected by reverse transcription-quantitative polymerase chain reaction, Western blotting and hematoxylin/eosin-staining. The levels of Wnt1, CTGF and DKK1 protein in serum were detected by enzyme-linked immunosorbent assay.ResultsCompared with BLM group, the WYHZTL formula and XAV-939 could significantly inhibit the thickness of the skin tissue of the SSc mouse model. The mRNA expression levels of GSK3β and DKK1 in the WYHZTL formula and XAV-939-treated group were significantly higher than those in the BLM group, while Wnt1, β-catenin, TCF4, cyclin D1, survivin, VEGF, CTGF, FN1, collagen I/III were decreased. Compared with BLM group, the protein expression levels of GSK3β and DKK1 in the WYHZTL formula and XAV-939-treated group were upregulated, while Wnt1, β-catenin, cyclin D1, survivin, CTGF, FN1, collagen I/III were downregulated. WYHZTL formula and XAV-939 could inhibit expression of Wnt1 and CTGF, but promoted DKK1 in serum. Furthermore, WYHZTL-H seemed more effective than WYHZTL-M and/or XAV-939 on regulating Wnt1, β-catenin, TCF4, GSK3β, DKK1, cyclin D1, survivin, VEGF, CTGF, FN1 and collagen I/III.ConclusionThis present study demonstrates that WYHZTL formula has anti-fibrosis effect in Bleomycin-induced SSc mouse model in a dosage-dependent manner, and the molecular mechanism may be related to the inhibition of Wnt/β-catenin signaling pathway.

Dataset Information

Adenosine A2a Receptor Blockade Diminishes Wnt/?-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

Publications

Adenosine A<sub>2a</sub> Receptor Blockade Diminishes Wnt/β-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

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