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

Academic Article

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.

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    Keywords

  • 3' Untranslated Regions, Blotting, Western, Cells, Cultured, Chromatin Immunoprecipitation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Hypertrophy, MicroRNAs, Muscle, Smooth, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Respiratory System, Reverse Transcriptase Polymerase Chain Reaction, Stress, Mechanical

    • Digital Object Identifier (doi)

    Author List

  • Mohamed JS; Lopez MA; Boriek AM

    • Start Page

  • 29336

    • End Page

  • 29347

    • Volume

  • 285

    • Issue

  • 38