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.
| Original language | English |
|---|---|
| Pages (from-to) | 997-1008 |
| Number of pages | 12 |
| Journal | European Heart Journal |
| Volume | 40 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Mar 21 2019 |
Cite this
Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy. / Costantino, Sarah; Akhmedov, Alexander; Melina, Giovanni; Mohammed, Shafeeq A; Othman, Alaa; Ambrosini, Samuele; Wijnen, Winandus J; Sada, Lidia; Ciavarella, Giuseppino M; Liberale, Luca; Tanner, Felix C; Matter, Christian M; Hornemann, Thorsten; Volpe, Massimo; Mechta-Grigoriou, Fatima; Camici, Giovanni G; Sinatra, Riccardo; Lüscher, Thomas F; Paneni, Francesco.
In: European Heart Journal, Vol. 40, No. 12, 21.03.2019, p. 997-1008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy
AU - Costantino, Sarah
AU - Akhmedov, Alexander
AU - Melina, Giovanni
AU - Mohammed, Shafeeq A
AU - Othman, Alaa
AU - Ambrosini, Samuele
AU - Wijnen, Winandus J
AU - Sada, Lidia
AU - Ciavarella, Giuseppino M
AU - Liberale, Luca
AU - Tanner, Felix C
AU - Matter, Christian M
AU - Hornemann, Thorsten
AU - Volpe, Massimo
AU - Mechta-Grigoriou, Fatima
AU - Camici, Giovanni G
AU - Sinatra, Riccardo
AU - Lüscher, Thomas F
AU - Paneni, Francesco
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
PY - 2019/3/21
Y1 - 2019/3/21
N2 - 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.
AB - 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.
U2 - 10.1093/eurheartj/ehy903
DO - 10.1093/eurheartj/ehy903
M3 - Article
C2 - 30629164
VL - 40
SP - 997
EP - 1008
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 12
ER -