| Source: |
el Azzouzi, H, Leptidis, S, Dirkx, E, Hoeks, J, van Bree, B, Brand, K, McClellan, EA, Poels, E, Sluimer, JC, van den Hoogenhof, MMG, Armand, AS, Yin, XK, Langley, S, Bourajjaj, M, Olieslagers, S, Krishnan, J, Vooijs, M, Kurihara, H, Stubbs, A, Pinto, YM, Krek, W, Mayr, M, Martins, PAD, Schrauwen, P & De Windt, LJ 2013, 'The Hypoxia-Inducible MicroRNA Cluster miR-199a similar to 214 Targets Myocardial PPAR delta and Impairs Mitochondrial Fatty Acid Oxidation', Cell Metabolism, vol. 18, no. 3, pp. 341-354. https://doi.org/10.1016/j.cmet.2013.08.009 |
| Description: |
Peroxisomeproliferator-activatedreceptor delta(PPAR delta) 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 similar to 214 and PPAR delta. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a similar to 214, which shares PPAR delta as common target. To address the significance of miR-199a similar to 214 induction and concomitant PPAR delta 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 similar to 214 actively represses cardiac PPAR delta 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. |