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Activation of peroxisome proliferation–activated receptor‐γ inhibits transforming growth factor‐β1‐induced airway smooth muscle cell proliferation by suppressing Smad–miR‐21 signaling
Author(s) -
Liu Lu,
Pan Yilin,
Zhai Cui,
Zhu Yanting,
Ke Rui,
Shi Wenhua,
Wang Jian,
Yan Xin,
Su Xiaofan,
Song Yang,
Gao Li,
Li Manxiang
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26839
Subject(s) - tensin , pten , cyclin d1 , smad , cell growth , foxo1 , pi3k/akt/mtor pathway , protein kinase b , signal transduction , gene knockdown , cancer research , microbiology and biotechnology , transforming growth factor , biology , smad2 protein , chemistry , cell cycle , cell , apoptosis , biochemistry , genetics
The aims of the current study were to examine the signaling mechanisms for transforming growth factor‐β1 (TGF‐β1)‐induced rat airway smooth muscle cell (ASMC) proliferation and to determine the effect of activation of peroxisome proliferation–activated receptor‐γ (PPAR‐γ) on TGF‐β1‐induced rat ASMC proliferation and its underlying mechanisms. TGF‐β1 upregulated microRNA 21 (miR‐21) expression by activating Smad2/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF‐β1–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‐γ activator, blocked TGF‐β1‐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‐γ 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.