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

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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)997-1008
Number of pages12
JournalEuropean Heart Journal
Volume40
Issue number12
DOIs
Publication statusPublished - Mar 21 2019

Cite this

Costantino, S., Akhmedov, A., Melina, G., Mohammed, S. A., Othman, A., Ambrosini, S., ... Paneni, F. (2019). Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy. European Heart Journal, 40(12), 997-1008. https://doi.org/10.1093/eurheartj/ehy903

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 journalArticle

Costantino, S, Akhmedov, A, Melina, G, Mohammed, SA, Othman, A, Ambrosini, S, Wijnen, WJ, Sada, L, Ciavarella, GM, Liberale, L, Tanner, FC, Matter, CM, Hornemann, T, Volpe, M, Mechta-Grigoriou, F, Camici, GG, Sinatra, R, Lüscher, TF & Paneni, F 2019, 'Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy', European Heart Journal, vol. 40, no. 12, pp. 997-1008. https://doi.org/10.1093/eurheartj/ehy903
Costantino S, Akhmedov A, Melina G, Mohammed SA, Othman A, Ambrosini S et al. Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy. European Heart Journal. 2019 Mar 21;40(12):997-1008. https://doi.org/10.1093/eurheartj/ehy903
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. / Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy. In: European Heart Journal. 2019 ; Vol. 40, No. 12. pp. 997-1008.
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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.",
author = "Sarah Costantino and Alexander Akhmedov and Giovanni Melina and Mohammed, {Shafeeq A} and Alaa Othman and Samuele Ambrosini and Wijnen, {Winandus J} and Lidia Sada and Ciavarella, {Giuseppino M} and Luca Liberale and Tanner, {Felix C} and Matter, {Christian M} and Thorsten Hornemann and Massimo Volpe and Fatima Mechta-Grigoriou and Camici, {Giovanni G} and Riccardo Sinatra and L{\"u}scher, {Thomas F} and Francesco Paneni",
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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

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VL - 40

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JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

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ER -