Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure

Andrea Raso; Ellen Dirkx; Leonne E. Philippen; Amaya Fernandez-Celis; Federica De Majo; Vasco Sampaio-Pinto; Marida Sansonetti; Rio Juni; Hamid el Azzouzi; Martina Calore; Nicole Bitsch; Servé Olieslagers; Martinus I.F.J. Oerlemans; Manon M. Huibers; Roel A. de Weger; Yolan J. Reckman; Yigal M. Pinto; Lorena Zentilin; Serena Zacchigna; Mauro Giacca; Paula A. da Costa Martins; Natalia López-Andrés; Leon J. De Windt

doi:10.1016/j.ymthe.2018.11.011

Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure

Andrea Raso, Ellen Dirkx, Leonne E. Philippen, Amaya Fernandez-Celis, Federica De Majo, Vasco Sampaio-Pinto, Marida Sansonetti, Rio Juni, Hamid el Azzouzi, Martina Calore, Nicole Bitsch, Servé Olieslagers, Martinus I.F.J. Oerlemans, Manon M. Huibers, Roel A. de Weger, Yolan J. Reckman, Yigal M. Pinto, Lorena Zentilin, Serena Zacchigna, Mauro GiaccaPaula A. da Costa Martins, Natalia López-Andrés, Leon J. De Windt^*

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

Abstract

Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.

Original language	English
Journal	Molecular Therapy
DOIs	https://doi.org/10.1016/j.ymthe.2018.11.011
Publication status	Accepted/In press - 1 Jan 2018

Keywords

adeno-associated vector
cardiac
heart failure
hypertrophy
microRNA
miR-148a
signaling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymthe.2018.11.011

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Raso, A., Dirkx, E., Philippen, L. E., Fernandez-Celis, A., De Majo, F., Sampaio-Pinto, V., Sansonetti, M., Juni, R., el Azzouzi, H., Calore, M., Bitsch, N., Olieslagers, S., Oerlemans, M. I. F. J., Huibers, M. M., de Weger, R. A., Reckman, Y. J., Pinto, Y. M., Zentilin, L., Zacchigna, S., ... De Windt, L. J. (Accepted/In press). Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.11.011

@article{6be001b22b714d64ad9ca94ee45959dd,

title = "Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure",

abstract = "Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.",

keywords = "adeno-associated vector, cardiac, heart failure, hypertrophy, microRNA, miR-148a, signaling",

author = "Andrea Raso and Ellen Dirkx and Philippen, {Leonne E.} and Amaya Fernandez-Celis and {De Majo}, Federica and Vasco Sampaio-Pinto and Marida Sansonetti and Rio Juni and {el Azzouzi}, Hamid and Martina Calore and Nicole Bitsch and Serv{\'e} Olieslagers and Oerlemans, {Martinus I.F.J.} and Huibers, {Manon M.} and {de Weger}, {Roel A.} and Reckman, {Yolan J.} and Pinto, {Yigal M.} and Lorena Zentilin and Serena Zacchigna and Mauro Giacca and {da Costa Martins}, {Paula A.} and Natalia L{\'o}pez-Andr{\'e}s and {De Windt}, {Leon J.}",

year = "2018",

month = jan,

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doi = "10.1016/j.ymthe.2018.11.011",

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Raso, A, Dirkx, E, Philippen, LE, Fernandez-Celis, A, De Majo, F, Sampaio-Pinto, V, Sansonetti, M, Juni, R, el Azzouzi, H, Calore, M, Bitsch, N, Olieslagers, S, Oerlemans, MIFJ, Huibers, MM, de Weger, RA, Reckman, YJ, Pinto, YM, Zentilin, L, Zacchigna, S, Giacca, M, da Costa Martins, PA, López-Andrés, N & De Windt, LJ 2018, 'Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure', Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.11.011

TY - JOUR

T1 - Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure

AU - Raso, Andrea

AU - Dirkx, Ellen

AU - Philippen, Leonne E.

AU - Fernandez-Celis, Amaya

AU - De Majo, Federica

AU - Sampaio-Pinto, Vasco

AU - Sansonetti, Marida

AU - Juni, Rio

AU - el Azzouzi, Hamid

AU - Calore, Martina

AU - Bitsch, Nicole

AU - Olieslagers, Servé

AU - Oerlemans, Martinus I.F.J.

AU - Huibers, Manon M.

AU - de Weger, Roel A.

AU - Reckman, Yolan J.

AU - Pinto, Yigal M.

AU - Zentilin, Lorena

AU - Zacchigna, Serena

AU - Giacca, Mauro

AU - da Costa Martins, Paula A.

AU - López-Andrés, Natalia

AU - De Windt, Leon J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.

AB - Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.

KW - adeno-associated vector

KW - cardiac

KW - heart failure

KW - hypertrophy

KW - microRNA

KW - miR-148a

KW - signaling

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U2 - 10.1016/j.ymthe.2018.11.011

DO - 10.1016/j.ymthe.2018.11.011

M3 - Article

AN - SCOPUS:85058372153

SN - 1525-0016

JO - Molecular Therapy

JF - Molecular Therapy

ER -

Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure

Abstract

Keywords

UN SDGs

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