Activation of PPAR-¦Á induces cell cycle arrest and inhibits transforming growth factor-¦Â1 induction of smooth muscle cell phenotype in 10T1/2 mesenchymal cells

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• 作者：Sheng-Chieh Lien^a ; ^b ; Shu-Yi Wei^a ; Shun-Fu Chang^c ; Margaret Dah-Tsyr Chang^b ; Jang-Yang Chang^d ; ^{jychang@nhri.org.tw} ; Jeng-Jiann Chiu^a ; ^{jjchiu@nhri.org.tw}
• 关键词：Cell cycle ; Mesenchymal cell ; PPAR-¦Á ; Smad ; Smooth muscle differentiation
• 刊名：Cellular Signalling
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：25
• 期：5
• 页码：1252-1263
• 全文大小：1387 K

文摘

Transforming growth factor-¦Â1 (TGF-¦Â1) regulates the cell cycle and the differentiation of mesenchymal cells into smooth muscle cells (SMCs). However, the precise intracellular signaling pathways involved in these processes have not been fully clarified. It has also been shown that there is an increase in TGF-¦Â1 expression in human atherosclerotic plaques. Furthermore, peroxisome proliferator-activated receptors (PPARs) and their agonists have recently gained more attention in the study of the pathogenesis of atherosclerosis. In this study, we examined the role of PPARs in the TGF-¦Â1-mediated cell cycle control and SMC phenotypic modulation of C3H10T1/2 (10T1/2) mesenchymal cells. The results showed the following: (1) the PI3K/Akt/p70S6K signaling cascade is involved in TGF-¦Â1-induced differentiation of 10T1/2 cells into cells with a SMC phenotype. (2) PPAR-¦Á agonists (i.e., WY14,643 and clofibrate), but not a PPAR-¦Ä/¦Â agonist (GW501516) or PPAR-¦Ã agonist (troglitazone), inhibit TGF-¦Â1-induced SMC markers and the DNA binding activity of serum response factor (SRF) in 10T1/2 cells. (3) WY14,643 and clofibrate inhibit the TGF-¦Â1 activation of the Smad3/Akt/P70S6K signaling cascade. (4) TGF-¦Â1-induced cell cycle arrest at the G₀/G₁ phases is mediated by Smad3 in 10T1/2 cells. (5) The PPAR-¦Á-mediated 10T1/2 cell cycle arrest at the G₀/G₁ phases is TGF-¦Â receptor independent. These results suggest that PPAR-¦Á mediates cell cycle control and TGF-¦Â1-induced SMC phenotypic changes in 10T1/2 cells.