title: The hypoxia-inducible microRNA cluster miR-199a∼214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation.
abstract: 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.
authors.affiliation: Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
authors.forename: Hamid
authors.initials: H
authors.lastname: el Azzouzi
authors.forename: Stefanos
authors.initials: S
authors.lastname: Leptidis
authors.forename: Ellen
authors.initials: E
authors.lastname: Dirkx
authors.forename: Joris
authors.initials: J
authors.lastname: Hoeks
authors.forename: Bianca
authors.initials: B
authors.lastname: van Bree
authors.forename: Karl
authors.initials: K
authors.lastname: Brand
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McClellan
authors.forename: Ella
authors.initials: E
authors.lastname: Poels
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.forename: Maarten M G
authors.initials: MM
authors.lastname: van den Hoogenhof
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Sarah
authors.initials: S
authors.lastname: Langley
authors.forename: Meriem
authors.initials: M
authors.lastname: Bourajjaj
authors.forename: Serve
authors.initials: S
authors.lastname: Olieslagers
authors.forename: Jaya
authors.initials: J
authors.lastname: Krishnan
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Andrew
authors.initials: A
authors.lastname: Stubbs
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D005810:Multigene Family; D009206:Myocardium / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical
chemical_list: D020413:3' Untranslated Regions; D005227:Fatty Acids; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D047494:PPAR delta