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, Serve 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 Lopez-Andres, Leon J. De Windt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Web of Science)

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 indilated 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 themouse 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 languageEnglish
Pages (from-to)584-599
Number of pages16
JournalMolecular Therapy
Volume27
Issue number3
DOIs
Publication statusPublished - 6 Mar 2019

Keywords

  • BRAIN NATRIURETIC PEPTIDE
  • CARDIAC-HYPERTROPHY
  • PLASMA CARDIOTROPHIN-1
  • INTERLEUKIN-6 FAMILY
  • IN-VIVO
  • GP130
  • EXPRESSION
  • GENE
  • SURVIVAL
  • MYOCYTES

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