title: Desmin regulates airway smooth muscle hypertrophy through early growth-responsive protein-1 and microRNA-26a.
abstract: Bronchial biopsies of asthmatic patients show a negative correlation desmin expression in airway smooth muscle cell (ASMC) and airway hyperresponsiveness. We previously showed that desmin is an intracellular load-bearing protein, which influences airway compliance, lung recoil, and airway contractile responsiveness (Shardonofsky, F. R., Capetanaki, Y., and Boriek, A. M. (2006) Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L890-L896). These results suggest that desmin may play an important role in ASMC homeostasis. Here, we report that ASMCs of desmin null mice (ASMCs(Des-/-)) show hypertrophy and up-regulation microRNA-26a (miR-26a). Knockdown of miR-26a in ASMCs(Des-/-) inhibits hypertrophy, whereas enforced expression of miR-26a in ASMCs(Des+/+) induces hypertrophy. We identify that Egr1 (early growth responsive protein-1) activates miR-26a promoter via enhanced phosphorylation of Erk1/2 in ASMCs(Des-/-). We show glycogen synthase kinase-3β (GSK-3β) as a target gene of miR-26a. Moreover, induction of ASMCs(Des-/-) hypertrophy by the Erk-1/2/Egr-1/miR-26a/GSK-3β pathway is consistent in human recombinant ASMCs, which stably suppresses 90% endogenous desmin expression. Overall, our data demonstrate a novel role for desmin as an anti-hypertrophic protein necessary for ASMC homeostasis and identifies desmin as a novel regulator of microRNA.
authors: Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Junaith S
authors: JS
authors: Mohamed
authors: Ameena
authors: A
authors: Hajira
authors: Zhenlin
authors: Z
authors: Li
authors: Denise
authors: D
authors: Paulin
authors: Aladin M
authors: AM
authors: Boriek
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003893:Desmin / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014132:Trachea / Q000166:cytology*
chemical_list: D003893:Desmin; D051766:Early Growth Response Protein 1; D035683:MicroRNAs; D038362:Glycogen Synthase Kinase 3