Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure
Raso, Andrea; Dirkx, Ellen; Philippen, Leonne E; Fernandez-Celis, Amaya; De Majo, Federica; Sampaio-Pinto, Vasco; Sansonetti, Marida; Juni, Rio; El Azzouzi, Hamid; Calore, Martina; Bitsch, Nicole; Olieslagers, Servé; Oerlemans, Martinus I F J; Huibers, Manon M; de Weger, Roel A; Reckman, Yolan J; Pinto, Yigal M; Zentilin, Lorena; Zacchigna, Serena; Giacca, Mauro; da Costa Martins, Paula A; López-Andrés, Natalia; De Windt, Leon J
(2019) Molecular Therapy, volume 27, issue 3, pp. 584 - 599
(Article)
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
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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.
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Keywords: adeno-associated vector, cardiac, heart failure, hypertrophy, microRNA, miR-148a, signaling, Drug Discovery, Genetics, Molecular Medicine, Molecular Biology, Pharmacology, Journal Article
ISSN: 1525-0016
Publisher: Nature Publishing Group
Note: Funding Information: E.D. is supported by VENI award 916-150-16 from the Netherlands Organization for Health Research and Development (ZonMW). V.S.-P. was funded by an individual fellowship (SFRH/BD/11799/2015) from FCT/Ministério da Ciência. P.A.d.C.M. is supported by a MEERVOUD grant from the Netherlands Organisation for Scientific Research (NWO) and is an Established Investigator of the Dutch Heart Foundation. N.L.-A. is supported by Miguel Servet contract CP13/00221 from the “Instituto de Salud Carlos III-FEDER.” L.J.D.W. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, ZonMw, and the Royal Netherlands Academy of Sciences. L.J.D.W. was further supported by grant 311549 from the European Research Council (ERC) and VICI award 918-156-47 from NWO. Funding Information: E.D. is supported by VENI award 916-150-16 from the Netherlands Organization for Health Research and Development (ZonMW). V.S.-P. was funded by an individual fellowship ( SFRH/BD/11799/2015 ) from FCT/Ministério da Ciência . P.A.d.C.M. is supported by a MEERVOUD grant from the Netherlands Organisation for Scientific Research (NWO) and is an Established Investigator of the Dutch Heart Foundation . N.L.-A. is supported by Miguel Servet contract CP13/00221 from the “Instituto de Salud Carlos III-FEDER.” L.J.D.W. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation , the Dutch Federation of University Medical Centers , ZonMw , and the Royal Netherlands Academy of Sciences . L.J.D.W. was further supported by grant 311549 from the European Research Council (ERC) and VICI award 918-156-47 from NWO . Publisher Copyright: © 2018 The Author(s)
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