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

• Published in: PloS one 2012-07, Vol.7 (7), p.e41574-e41574
• Main Authors: Chen, Hao, Untiveros, Gustavo M, McKee, Laurel A K, Perez, Jessica, Li, Jing, Antin, Parker B, Konhilas, John P
• Format: Article
• Language: English
• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041574

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.