The Hypoxia-Inducible MicroRNA Cluster miR-199a∼214 Targets Myocardial PPARδ and Impairs Mitochondrial Fatty Acid Oxidation

• DOI: 10.1016/j.cmet.2013.08.009
• Publication Date: 2013-09-03T15:45:19Z
• Authors: Hamid el Azzouzi; Stefanos Leptidis; Ellen Dirkx; Joris Hoeks; Bianca van Bree; Karl Brand; Elizabeth A. McCl...; Ella Poels; Judith C. Sluimer; Maarten M.G. van ...; Anne-Sophie Armand; Xiaoke Yin; Sarah Langley; Meriem Bourajjaj; Serve Olieslagers; Jaya Krishnan; Marc Vooijs; Hiroki Kurihara; Andrew Stubbs; Yigal M. Pinto; Wilhelm Krek; Manuel Mayr; Paula A. da Costa...; Patrick Schrauwen; Leon J. De Windt
• Keywords: Heart Failure; 0303 health sciences; Base Sequence; Physiology; Gene Expression Profiling; Myocardium; Fatty Acids; Cell Biology; Oligonucleotides, Antisense; Mitochondria; 3. Good health; Mice; MicroRNAs; 03 medical and health sciences; Multigene Family; Animals; Humans; Gene Silencing; PPAR delta; Stress, Mechanical; Hypoxia; Molecular Biology; 3' Untranslated Regions; Oxidation-Reduction

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.