Journal
EUROPEAN HEART JOURNAL
Volume 40, Issue 12, Pages 997-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehy903
Keywords
Obesity; Myocardial steatosis; Lipotoxic damage; Metabolic cardiomyopathy; MicroRNAs; Epigenetics
Categories
Funding
- H.H. Sheikh Khalifa bin Hamad Al Thani Foundation Assistant Professorship at the Faculty of Medicine, University of Zurich
- Zurich Heart House
- Swiss Heart Foundation
- Swiss Life Foundation
- Kurt und Senta-Hermann Stiftung
- EMDO Stiftung
- Schweizerische Diabetes-Stiftung
- Holcim Foundation
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Aims Metabolic cardiomyopathy (MC)characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damageis an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC. Methods and results JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPAR promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPAR activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPAR signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPAR-dependent genes, and echocardiographic indices of LV dysfunction. Conclusion miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.
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