Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25

Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. We hypothesized that components of the adenosine monophosphate-activated kinase (AMPK) pathway are targeted by miRs and alter AMPK signaling during pathologi...

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Published in:	PloS one Vol. 7; no. 7; p. e41574
Main Authors:	Chen, Hao, Untiveros, Gustavo M, McKee, Laurel A K, Perez, Jessica, Li, Jing, Antin, Parker B, Konhilas, John P
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 23-07-2012 Public Library of Science (PLoS)
Subjects:	Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adenosine kinase Adenosine monophosphate Adenylate Kinase - metabolism AMP Analysis Animals Base Sequence Biology Cardiomyopathy Cardiomyopathy, Hypertrophic - drug therapy Cardiomyopathy, Hypertrophic - genetics Cardiomyopathy, Hypertrophic - metabolism Cardiomyopathy, Hypertrophic - pathology Cardiovascular disease Cell Line Coronary artery disease Development and progression Disease Progression Enzyme Activation - genetics Fatty acids Gene expression Heart Heart diseases Heart failure Heart hypertrophy Humans Hypertrophy Hypoxia Interrogation Kinases LKB1 protein Male Metabolism Mice MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Molecular Targeted Therapy Myocardium - metabolism Myocardium - pathology Nitric oxide Organ Specificity Overexpression Phosphorylation Physiology Protein expression Protein-Serine-Threonine Kinases - metabolism Proteins Pulmonary hypertension Ribonucleic acid RNA Rodents Signal Transduction - genetics Signaling siRNA Up-Regulation - genetics United States > US Arizona
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Summary:	Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. We hypothesized that components of the adenosine monophosphate-activated kinase (AMPK) pathway are targeted by miRs and alter AMPK signaling during pathological cardiac stress. Using a mouse model of hypertrophic cardiomyopathy (HCM), we demonstrated early elevation of miR-195 and miR-451 in HCM hearts, which targets MO25, a central component of the MO25/STRAD/LKB1 complex that acts as an upstream kinase for AMPK. We show functional targeting of MO25 by miR-195 and -451. Further in vitro interrogation of MO25 as a functional target validated this hypothesis where over-expression of miR-195 in C2C12 cells knocked down MO25 expression levels and downstream AMPK signaling (phosphorylation of Acetyl CoA carboxylase [ACC] and AMPK activity assay), similar to MO25 knockdown in C2C12 cells by siRNA. Parallel changes were measured in 60 day R403Q HCM male hearts that were rescued by short-term administration of AICAR, an AMPK agonist. Elevated miR-195 targets the LKB1/AMPK signaling axis in HCM progression and implicates a functional role in HCM disease progression. MiR-195 may serve as potential therapeutics or therapeutic targets for heart disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: HC JPK PBA. Performed the experiments: HC GMU LAKM JP JL. Analyzed the data: HC JPK PBA. Contributed reagents/materials/analysis tools: JPK PBA JL. Wrote the paper: HC JPK PBA.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0041574