title: Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Physiology, University of Arizona, Tucson, Arizona, United States of America.
authors: Hao
authors: H
authors: Chen
authors: Gustavo M
authors: GM
authors: Untiveros
authors: Laurel A K
authors: LA
authors: McKee
authors: Jessica
authors: J
authors: Perez
authors: Jing
authors: J
authors: Li
authors: Parker B
authors: PB
authors: Antin
authors: John P
authors: JP
authors: Konhilas
mesh_terms: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000629659:Cab39 protein, mouse; D002135:Calcium-Binding Proteins; C569389:MIRN195a microRNA, mouse; D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase