A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses.
A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses.
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DOI：
10.1136/annrheumdis-2012-202716
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发表时间：
2014-02
影响因子：
27.4
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Wei J;Zhu H;Komura K;Lord G;Tomcik M;Wang W;Doniparthi S;Tamaki Z;Hinchcliff M;Distler JH;Varga J
Persistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis (SSc), and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) exerts potent fibrotic activities. The synthetic triterpenoid oleanane 2-cyano-3,12-dioxoolean-1,9-dien-28-oic (CDDO) is a PPAR-γ agonist with potential effects on TGF-β signaling and dermal fibrosis. To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma. The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of type I constitutively active TGF-β receptor was evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the anti-fibrotic effects of CDDO, explanted skin fibroblasts cultured in 2-dimensional monolayers or in 3-dimensional full-thickness human skin equivelants were studied. CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in 3-dimensional human skin equivalents. In 2-dimensional monolayer cultures, CDDO abrogated fibrogenic responses in explanted normal human skin fibroblasts. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated collagen synthesis. Remarkably, the anti-fibrotic effects of CDDO were independent of PPAR-γ. The PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signaling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
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影响因子：
6.5
作者：
Karnik, Pratima;Tekeste, Zenar;Mirmirani, Paradi
通讯作者：
Mirmirani, Paradi
影响因子：
2.7
作者：
Honda, T;Rounds, BV;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
5
作者：
Kawai, Toru;Masaki, Takao;Yorioka, Noriaki
通讯作者：
Yorioka, Noriaki
影响因子：
--
作者：
Ghosh, AK;Bhattacharyya, S;Varga, J
通讯作者：
Varga, J
硬皮病皮肤的基因表达特征中的分子亚群。
影响因子：
3.7
作者：
Milano A;Pendergrass SA;Sargent JL;George LK;McCalmont TH;Connolly MK;Whitfield ML
通讯作者：
Whitfield ML