Desmin Regulates Airway Smooth Muscle Hypertrophy through Early Growth-responsive Protein-1 and MicroRNA-26a

被引：29

作者：

Mohamed, Junaith S. ^{[1
]}

Hajira, Ameena ^{[1
]}

Li, Zhenlin ^{[2
]}

Paulin, Denise ^{[2
]}

Boriek, Aladin M. ^{[1
]}

机构：

[1] Baylor Coll Med, Dept Med, Sect Pulm Crit Care & Sleep Med, Houston, TX 77030 USA

[2] Univ Paris 06, UR4, F-75005 Paris, France

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 50期

基金：

美国国家科学基金会;

关键词：

GLYCOGEN-SYNTHASE KINASE-3-BETA; CARDIAC-HYPERTROPHY; KINASE; 3-BETA; EGR-1; EXPRESSION; MOUSE MODEL; GENE; PHOSPHORYLATION; TRANSCRIPTION; CELLS; DIFFERENTIATION;

D O I：

10.1074/jbc.M111.235127

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Bronchial biopsies of asthmatic patients show a negative correlation between 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-3 beta (GSK-3 beta) as a target gene of miR-26a. Moreover, induction of ASMCs(Des-/-) hypertrophy by the Erk-1/2/Egr-1/miR-26a/GSK-3 beta 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.

引用

页码：43394 / 43404

页数：11

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