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 - 2019/3/6
Y1 - 2019/3/6
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. Raso et al. show that miR-148a is elevated in concentric hypertrophy and decreased in dilated cardiomyopathy. Adeno-associated viral delivery of miR-148a protects the mouse heart from cardiac dilation. Mechanistically, miR-148a regulates the sensitivity of the heart to extracellular cytokines.
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. Raso et al. show that miR-148a is elevated in concentric hypertrophy and decreased in dilated cardiomyopathy. Adeno-associated viral delivery of miR-148a protects the mouse heart from cardiac dilation. Mechanistically, miR-148a regulates the sensitivity of the heart to extracellular cytokines.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85058372153&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30559069
U2 - https://doi.org/10.1016/j.ymthe.2018.11.011
DO - https://doi.org/10.1016/j.ymthe.2018.11.011
M3 - Article
C2 - 30559069
SN - 1525-0016
VL - 27
SP - 584
EP - 599
JO - Molecular therapy
JF - Molecular therapy
IS - 3
ER -