Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation

Consuelo Torrini, Ryan John Cubero, Ellen Dirkx, Luca Braga, Hashim Ali, Giulia Prosdocimo, Maria Ines Gutierrez, Chiara Collesi, Danilo Licastro, Lorena Zentilin, Miguel Mano, Serena Zacchigna, Michele Vendruscolo, Matteo Marsili, Areejit Samal, Mauro Giacca*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Web of Science)

Abstract

Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase beta-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.

Original languageEnglish
Pages (from-to)2759-2771.e5
Number of pages18
JournalCell Reports
Volume27
Issue number9
DOIs
Publication statusPublished - 28 May 2019

Keywords

  • HEART REGENERATION
  • HIPPO
  • ACTIN
  • GROWTH
  • COFILIN
  • PHOSPHORYLATION
  • CLUSTER
  • MIRNAS
  • YAP1

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