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

被引：228

作者：

el Azzouzi, Hamid ^{[1
,4
]}

Leptidis, Stefanos ^{[1
,5
]}

Dirkx, Ellen ^{[1
]}

Hoeks, Joris ^{[2
]}

van Bree, Bianca ^{[2
]}

Brand, Karl ^{[6
,7
]}

McClellan, Elizabeth A. ^{[7
]}

Poels, Ella ^{[1
]}

Sluimer, Judith C. ^{[3
]}

van den Hoogenhof, Maarten M. G. ^{[8
]}

Armand, Anne-Sophie ^{[9
]}

Yin, Xiaoke ^{[10
]}

Langley, Sarah ^{[10
]}

Bourajjaj, Meriem ^{[5
]}

Olieslagers, Serve ^{[1
]}

Krishnan, Jaya ^{[11
]}

Vooijs, Marc ^{[12
]}

Kurihara, Hiroki ^{[13
]}

Stubbs, Andrew ^{[7
]}

Pinto, Yigal M. ^{[8
]}

Krek, Wilhelm ^{[11
]}

Mayr, Manuel ^{[10
]}

Martins, Paula A. da Costa ^{[1
]}

Schrauwen, Patrick ^{[2
]}

De Windt, Leon J. ^{[1
]}

机构：

[1] Maastricht Univ, Dept Cardiol, CARIM Sch Cardiovasc Dis, NL-6229 ER Maastricht, Netherlands

[2] Maastricht Univ, Dept Human Biol, NUTRIM Sch Nutr Toxicol & Metab, NL-6229 ER Maastricht, Netherlands

[3] Maastricht Univ, Dept Pathol, CARIM Sch Cardiovasc Dis, NL-6229 ER Maastricht, Netherlands

[4] Univ Med Ctr Utrecht, Dept Cardiol, NL-3584 CX Utrecht, Netherlands

[5] Royal Netherlands Acad Sci, Interuniv Cardiol Inst Netherlands, NL-3511 GC Utrecht, Netherlands

[6] Erasmus Univ, Med Ctr, Dept Cardiol, NL-3015 CE Rotterdam, Netherlands

[7] Erasmus Univ, Med Ctr, Dept Bioinformat, NL-3015 CE Rotterdam, Netherlands

[8] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[9] Univ Paris 05, UMR CNRS 8194, Ctr Etud Sensori Motricite, F-75270 Paris, France

[10] Kings Coll London, Kings BHF Ctr, London WC2R 2LS, England

[11] ETH, Inst Mol Hlth Sci, CH-8092 Zurich, Switzerland

[12] Maastricht Univ, Med Ctr, Dept Radiat Oncol, MAASTRO Lab, NL-6202 AZ Maastricht, Netherlands

[13] Univ Tokyo, Dept Physiol Chem & Metab, Tokyo 1138654, Japan

来源：

CELL METABOLISM | 2013年 / 18卷 / 03期

基金：

欧洲研究理事会;

关键词：

ACTIVATED RECEPTOR-DELTA; CARDIAC-HYPERTROPHY; HEART-FAILURE; IN-VIVO; ISCHEMIC-INJURY; MOUSE HEART; TWIST; ANGIOGENESIS; METASTASIS; EXPRESSION;

D O I：

10.1016/j.cmet.2013.08.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：341 / 354

页数：14

共 42 条

[1]

MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death [J].