Mechanical stretch up-regulates microRNA-26a and induces human airway smooth muscle hypertrophy by suppressing glycogen synthase kinase-3β

Junaith Mohamed, Michael A. Lopez, Aladin M. Boriek

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Airway smooth muscle hypertrophy is one of the hallmarks of airway remodeling in severe asthma. Several human diseases have been now associated with dysregulated microRNA (miRNA) expression. miRNAs are a class of small non-coding RNAs, which negatively regulate gene expression at the post-transcriptional level. Here, we identify miR-26a as a hypertrophic miRNA of human airway smooth muscle cells (HASMCs). We show that stretch selectively induces the transcription of miR-26a located in the locus 3p21.3 of human chromosome 3. The transcription factor CCAAT enhancer-binding protein α (C/EBPα) directly activates miR-26a expression through the transcriptional machinery upon stretch. Furthermore, stretch or enforced expression of miR-26a induces HASMC hypertrophy, and miR-26 knockdown reverses this effect, suggesting that miR-26a is a hypertrophic gene. We identify glycogen synthase kinase-3β (GSK-3β), an anti-hypertrophic protein, as a target gene of miR-26a. Luciferase reporter assays demonstrate that miR-26a directly interact with the 3′-untranslated repeat of the GSK-3β mRNA. Stretch or enforced expression of miR-26a attenuates the endogenous GSK-3β protein levels followed by the induction of HASMC hypertrophy. miR-26 knockdown reverses this effect, suggesting that miR-26a-induced hypertrophy occurs via its target gene GSK-3β. Overall, as a first time, our study unveils that miR-26a is a mechanosensitive gene, and it plays an important role in the regulation of HASMC hypertrophy.

Original languageEnglish (US)
Pages (from-to)29336-29347
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number38
DOIs
StatePublished - Sep 17 2010

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Glycogen Synthase Kinase 3
MicroRNAs
Hypertrophy
Smooth Muscle
Muscle
Up-Regulation
Smooth Muscle Myocytes
Genes
Cells
CCAAT-Enhancer-Binding Proteins
Airway Remodeling
Small Untranslated RNA
Chromosomes, Human, Pair 3
Human Chromosomes
Time and motion study
Luciferases
Transcription
Chromosomes
Proteins
Gene expression

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Mechanical stretch up-regulates microRNA-26a and induces human airway smooth muscle hypertrophy by suppressing glycogen synthase kinase-3β. / Mohamed, Junaith; Lopez, Michael A.; Boriek, Aladin M.

In: Journal of Biological Chemistry, Vol. 285, No. 38, 17.09.2010, p. 29336-29347.

Research output: Contribution to journalArticle

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