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Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation

Consuelo Torrini1, Ryan John Cubero2, Ellen Dirkx1

  • 1Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.

Cell Reports
|May 30, 2019
PubMed

Insights

Specific microRNAs (miRNAs) promote heart regeneration by activating Yes-associated protein (YAP) and modulating the actin cytoskeleton. These findings offer new avenues for treating heart failure.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Regenerative Medicine

Background:

  • Loss of cardiomyocytes after myocardial infarction leads to heart failure.
  • MicroRNAs (miRNAs) have shown potential in stimulating cardiac regeneration in preclinical models.
  • Identifying the precise molecular mechanisms underlying miRNA-mediated cardiac repair is crucial.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which specific miRNAs promote cardiomyocyte proliferation and cardiac regeneration.
  • To investigate the role of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP) in miRNA-induced cardiac repair.
  • To identify novel therapeutic targets for heart failure treatment.

Main Methods:

  • High-throughput screening of miRNAs for pro-proliferative effects on cardiomyocytes.
  • Analysis of nuclear localization of YAP and expression of YAP-responsive genes.
  • Luciferase reporter assays to validate miRNA targeting of TAOK1 and β-TrCP mRNAs.
  • Assessment of filamentous actin dynamics and its impact on YAP translocation.
  • In vivo studies in mouse models of myocardial infarction (not explicitly detailed in abstract but implied by context).

Main Results:

  • Effective pro-proliferative miRNAs, including miR-199a-3p, activate nuclear translocation of YAP.
  • miR-199a-3p directly targets TAOK1 and β-TrCP mRNAs, inhibiting the Hippo pathway and preventing YAP degradation.
  • Several pro-proliferative miRNAs inhibit Cofilin2, preventing actin depolymerization and promoting YAP nuclear translocation.
  • Activation of YAP and actin cytoskeleton modulation are key mechanisms for miRNA-induced cardiomyocyte proliferation.

Conclusions:

  • Yes-associated protein (YAP) activation is a central mechanism for pro-proliferative miRNAs in cardiac regeneration.
  • Modulation of the actin cytoskeleton by miRNAs plays a significant role in YAP activation and cardiomyocyte proliferation.
  • These findings highlight the therapeutic potential of specific miRNAs and YAP pathway modulation for treating heart failure.
Keywords:
Cofilin2HippoYAPcardiomyocytecell cyclecytoskeletonmicroRNAregeneration

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