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TGF\u2010\u03b21 upregulated microRNA 21 (miR\u201021) expression by activating Smad2\/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF\u2010\u03b21\u2013Smad\u2013miR\u201021 signaling also downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and thus de\u2010repressed the PI3K\u2013Akt pathway. Depletion of PTEN reduced the nuclear FOXO1 protein level without affecting its mRNA level. Inhibition of the PI3K\u2013Akt pathway or proteasome function reversed PTEN knockdown\u2010induced 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\u2010\u03b3 activator, blocked TGF\u2010\u03b21\u2010induced activation of Smad2\/3 and its downstream targets changes of miR\u201021, PTEN, Akt, FOXO1, and cyclin D1, resulting in the inhibition of rat ASMC proliferation. Our study suggests that the activation of PPAR\u2010\u03b3 inhibits rat ASMC proliferation by suppressing Smad\u2013miR\u201021 signaling and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.<\/jats:p>","DOI":"10.1002\/jcp.26839","type":"journal-article","created":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T12:16:15Z","timestamp":1534940175000},"page":"669-681","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Activation of peroxisome proliferation\u2013activated receptor\u2010\u03b3 inhibits transforming growth factor\u2010\u03b21\u2010induced airway smooth muscle cell proliferation by suppressing Smad\u2013miR\u201021 signaling"],"prefix":"10.1002","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2683-7215","authenticated-orcid":false,"given":"Lu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of 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