Activation of peroxisome proliferation–activated receptor-γ inhibits transforming growth factor-β1-induced airway smooth muscle cell proliferation by suppressing Smad–miR-21 signaling

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)669-681
Number of pages13
JournalJournal of Cellular Physiology
Volume234
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Activation of peroxisome proliferation–activated receptor-γ inhibits transforming growth factor-β1-induced airway smooth muscle cell proliferation by suppressing Smad–miR-21 signaling'. Together they form a unique fingerprint.

Cite this