2013-09-03
The Hypoxia-Inducible MicroRNA Cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation
Publication
Publication
Cell Metabolism , Volume 18 - Issue 3 p. 1- 14
Summary 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.
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| doi.org/10.1016/j.cmet.2013.08.009, hdl.handle.net/1765/41412 | |
| Cell Metabolism | |
| Organisation | Erasmus MC: University Medical Center Rotterdam |
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El Azzouzi, H., Leptidis, S., Dirkx, E., van den Hoek, J., van Bree, B., Brand, K., McClellan, E., Poels, E., Sluimer, J., van den Hoogenhof, M., Armand, A.-S., Yin, X., Langley, S., Bourajjaj, M., Olieslagers, S., Krishnan, J., Vooijs, M., Kurihara, H., Stubbs, A., … de Windt, L. (2013). The Hypoxia-Inducible MicroRNA Cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metabolism, 18(3), 1–14.https://doi.org/10.1016/j.cmet.2013.08.009 |
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