title: Activation of PPAR-α induces cell cycle arrest and inhibits transforming growth factor-β1 induction of smooth muscle cell phenotype in 10T1/2 mesenchymal cells.
abstract: Transforming growth factor-β1 (TGF-β1) 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-β1 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-β1-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-β1-induced differentiation of 10T1/2 cells into cells with a SMC phenotype. (2) PPAR-α agonists (i.e., WY14,643 and clofibrate), but not a PPAR-δ/β agonist (GW501516) or PPAR-γ agonist (troglitazone), inhibit TGF-β1-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-β1 activation of the Smad3/Akt/P70S6K signaling cascade. (4) TGF-β1-induced cell cycle arrest at the G0/G1 phases is mediated by Smad3 in 10T1/2 cells. (5) The PPAR-α-mediated 10T1/2 cell cycle arrest at the G0/G1 phases is TGF-β receptor independent. These results suggest that PPAR-α mediates cell cycle control and TGF-β1-induced SMC phenotypic changes in 10T1/2 cells.
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Sheng-Chieh
authors: SC
authors: Lien
authors: Shu-Yi
authors: SY
authors: Wei
authors: Shun-Fu
authors: SF
authors: Chang
authors: Margaret Dah-Tsyr
authors: MD
authors: Chang
authors: Jang-Yang
authors: JY
authors: Chang
authors: Jeng-Jiann
authors: JJ
authors: Chiu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002994:Clofibrate / Q000494:pharmacology; D056741:Cyclin D / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D056741:Cyclin D; D047493:PPAR alpha; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D026362:Serum Response Factor; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C006253:pirinixic acid; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D051358:Cyclin-Dependent Kinase 4; D000077293:Receptor, Transforming Growth Factor-beta Type I; D002994:Clofibrate