Sarah Costantino1, Alexander Akhmedov1, Giovanni Melina2, Shafeeq A Mohammed1, Alaa Othman3, Samuele Ambrosini1, Winandus J Wijnen1, Lidia Sada4, Giuseppino M Ciavarella4, Luca Liberale1,5, Felix C Tanner6, Christian M Matter1,6, Thorsten Hornemann3, Massimo Volpe4,7, Fatima Mechta-Grigoriou8,9, Giovanni G Camici1,6, Riccardo Sinatra2, Thomas F Lüscher1,10, Francesco Paneni1,6. 1. Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Switzerland. 2. Department of Cardiac Surgery, Sant'Andrea Hospital, "Sapienza" University, Via di Grottarossa, 1035, Rome, Italy. 3. Institute for Clinical Chemistry, University Hospital Zürich, Ramistrasse 100, Zurich, Switzerland. 4. Department of Clinical and Molecular Medicine, Cardiology Unit, Faculty of Medicine and Psychology, "Sapienza" University, Via di Grottarossa, 1035, Rome, Italy. 5. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6, Genoa, Italy. 6. University Heart Center, Cardiology, University Hospital Zürich, Ramistrasse 100, Zurich, Switzerland. 7. IRCCS Neuromed, Pozzilli, Via Atinense, 18, Pozzilli (IS), Italy. 8. Institut Curie, Stress and Cancer Laboratory, Equipe Labelisée par la Ligue Nationale contre le Cancer, PSL Research University, 26, rue d'Ulm, Paris, France. 9. Inserm, U830, 26, rue d'Ulm, Paris, France. 10. Cardiology, Royal Brompton and Harefield Hospitals and Imperial College, London, UK.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obesepatients. 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 obesemice. 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. Obesemice 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 obesemice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obesepatients 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 obesepatients. Published on behalf of the European Society of Cardiology. All rights reserved.