Activation of peroxisome proliferation-activated receptor-gamma inhibits transforming growth factor-beta 1-induced airway smooth muscle cell proliferation by suppressing Smad-miR-21 signaling

作者：Liu, Lu; Pan, Yilin; Zhai, Cui; Zhu, Yanting; Ke, Rui; Shi, Wenhua; Wang, Jian; Yan, Xin; Su, Xiaofan; Song, Yang; Gao, Li; Li, Manxiang^*

来源：Journal of Cellular Physiology, 2019, 234(1): 669-681.

DOI：10.1002/jcp.26839

• airway smooth muscle cells
• FOXO1
• microRNA 21
• peroxisome proliferation-activated receptor-gamma
• phosphatase and tensin homolog deleted on chromosome ten

The aims of the current study were to examine the signaling mechanisms for transforming growth factor-beta 1 (TGF-beta 1)-induced rat airway smooth muscle cell (ASMC) proliferation and to determine the effect of activation of peroxisome proliferation-activated receptor-gamma (PPAR-gamma) on TGF-beta 1-induced rat ASMC proliferation and its underlying mechanisms. TGF-beta 1 upregulated microRNA 21 (miR-21) expression by activating Smad2/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF-beta 1-Smad-miR-21 signaling also downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and thus de-repressed the PI3K-Akt pathway. Depletion of PTEN reduced the nuclear FOXO1 protein level without affecting its mRNA level. Inhibition of the PI3K-Akt pathway or proteasome function reversed PTEN knockdown-induced nuclear FOXO1 protein reduction. Our study further showed that loss of FOXO1 increased cyclin D1 expression, leading to rat ASMC proliferation. Preincubation of rat ASMCs with pioglitazone, a PPAR-gamma activator, blocked TGF-beta 1-induced activation of Smad2/3 and its downstream targets changes of miR-21, PTEN, Akt, FOXO1, and cyclin D1, resulting in the inhibition of rat ASMC proliferation. Our study suggests that the activation of PPAR-gamma inhibits rat ASMC proliferation by suppressing Smad-miR-21 signaling and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.

• 出版日期2019-1
• 单位西安交通大学