TY - JOUR
T1 - The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation
AU - El Azzouzi, Hamid
AU - Leptidis, Stefanos
AU - Dirkx, Ellen
AU - Hoeks, Joris
AU - van Bree, Bianca
AU - Brand, Karl
AU - McClellan, Elizabeth A.
AU - Poels, Ella
AU - Sluimer, Judith C.
AU - van den Hoogenhof, Maarten M. G.
AU - Armand, Anne-Sophie
AU - Yin, Xiaoke
AU - Langley, Sarah
AU - Bourajjaj, Meriem
AU - Olieslagers, Serve
AU - Krishnan, Jaya
AU - Vooijs, Marc
AU - Kurihara, Hiroki
AU - Stubbs, Andrew
AU - Pinto, Yigal M.
AU - Krek, Wilhelm
AU - Mayr, Manuel
AU - da Costa Martins, Paula A.
AU - Schrauwen, Patrick
AU - de Windt, Leon J.
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.cmet.2013.08.009
DO - https://doi.org/10.1016/j.cmet.2013.08.009
M3 - Article
C2 - 24011070
SN - 1550-4131
VL - 18
SP - 341
EP - 354
JO - Cell metabolism
JF - Cell metabolism
IS - 3
ER -