Abstract
BackgroundRecently, 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.Methodology/Principal FindingsUsing 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/SignificanceElevated 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.
Highlights
MicroRNAs are small, noncoding RNAs 18–25 nucleotides in length that negatively regulate gene expression in a sequence-specific manner
Only two AMPK kinases (AMPKKs) have been identified in the heart: the tumor suppressor kinase LKB1 [15,16] and a calmodulin-dependent protein kinase kinase (CamKK) [17]
We show that miR-195 and 451 are up-regulated in R403Q hypertrophic cardiomyopathy (HCM) male hearts, which targets MO25, a central component in the LKB1/AMPK signaling pathway
Summary
MicroRNAs (miR) are small, noncoding RNAs 18–25 nucleotides (nt) in length that negatively regulate gene expression in a sequence-specific manner. MiRs have emerged as prominent players in the development of cardiac hypertrophy and heart failure [4,5,6] and may serve as potential therapeutics or therapeutic targets for heart disease [7,8,9]. Recent studies show that AMP-kinase (AMPK) is a critical regulator of cellular metabolism and cardiac hypertrophy [12,13,14]. Direct phosphorylation at Thr-172 (a subunit) by upstream AMPK kinases (AMPKKs) is required for activation and is a key mechanism by which cardiac AMPK is activated during times of metabolic stress. Activation of AMPK turns off energy consuming processes, such as protein synthesis, while switching on ATP-generating mechanisms, such as fatty acid oxidation (FAO) and glycolysis [20]. 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
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