The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation

Cell Metab. 2013 Sep 3;18(3):341-54. doi: 10.1016/j.cmet.2013.08.009.


Peroxisome proliferator-activated receptor δ (PPARδ) is a critical regulator of energy metabolism in the heart. Here, we propose a mechanism that integrates two deleterious characteristics of heart failure, hypoxia and a metabolic shift toward glycolysis, involving the microRNA cluster miR-199a∼214 and PPARδ. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a∼214, which shares PPARδ as common target. To address the significance of miR-199a∼214 induction and concomitant PPARδ repression, we performed antagomir-based silencing of both microRNAs and subjected mice to biomechanical stress to induce heart failure. Remarkably, antagomir-treated animals displayed improved cardiac function and restored mitochondrial fatty acid oxidation. Taken together, our data suggest a mechanism whereby miR-199a∼214 actively represses cardiac PPARδ expression, facilitating a metabolic shift from predominant reliance on fatty acid utilization in the healthy myocardium toward increased reliance on glucose metabolism at the onset of heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism*
  • Gene Expression Profiling
  • Gene Silencing
  • Heart Failure / etiology
  • Heart Failure / metabolism
  • Humans
  • Hypoxia*
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Multigene Family
  • Myocardium / metabolism*
  • Oligonucleotides, Antisense / metabolism
  • Oxidation-Reduction
  • PPAR delta / antagonists & inhibitors
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • Stress, Mechanical


  • 3' Untranslated Regions
  • Fatty Acids
  • MicroRNAs
  • Oligonucleotides, Antisense
  • PPAR delta