Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

Abstract

AIMS:

Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is 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 PPARγ 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 PPARγ 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/PPARγ 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 PPARγ-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.

• Authors: Sarah Costantino, Alexander Akhmedov, Giovanni Melina, Shafeeq A Mohammed, Alaa Othman, Samuele Ambrosini, Winandus J Wijnen, Lidia Sada, Giuseppino M Ciavarella, Luca Liberale, Felix C Tanner, Christian M Matter, Thorsten Hornemann, Massimo Volpe, Fatima Mechta-Grigoriou, Giovanni G Camici, Riccardo Sinatra, Thomas F Lüscher, Francesco Paneni
• Journal: European heart journal (Eur Heart J) Vol. 40 Issue 12 Pg. 997-1008 (03 21 2019) ISSN: 1522-9645 [Electronic] England
• PMID: 30629164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• MIRN494 microRNA, rat
• MicroRNAs
• PPAR gamma
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• Triglycerides
• junD protein, mouse

Topics

• Animals
• Cardiomyopathies (complications, metabolism, physiopathology)
• Case-Control Studies
• Diet, High-Fat
• Down-Regulation
• Heart Failure (etiology)
• Humans
• Lipid Metabolism
• Mice
• MicroRNAs (metabolism)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Obesity (complications)
• PPAR gamma (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Rats
• Transcription Factor AP-1 (metabolism)
• Transcriptional Activation
• Triglycerides (metabolism)
• Ventricular Dysfunction, Left (diagnostic imaging, physiopathology, prevention & control)