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

内科学 医学 内分泌学 脂肪变性 CD36 心力衰竭 心肌病 激活剂(遗传学) 脂质代谢 受体
作者
Sarah Costantino,Alexander Akhmedov,Giovanni Melina,Sabira Mohammed,Alaa Othman,Samuele Ambrosini,Winandus J Wijnen,Lidia Sada,Giuseppino Massimo 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
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:40 (12): 997-1008 被引量:68
标识
DOI:10.1093/eurheartj/ehy903
摘要

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. 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. 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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