1. Developmental Biology
  2. Stem Cells and Regenerative Medicine
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Retinoic acid signaling is directly activated in cardiomyocytes and protects mouse hearts from apoptosis after myocardial infarction

Research Article
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Cite this article as: eLife 2021;10:e68280 doi: 10.7554/eLife.68280

Abstract

Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line using CreERT2 technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of the Aldh1a1/a2/a3 genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis reveals Tgm2 and Ace1, two genes with well-established links to cardiac repair, as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease.

Data availability

RNA sequencing data have been deposited in GEO under accession code GSE161429

The following data sets were generated

Article and author information

Author details

  1. Fabio Da Silva

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8983-2238
  2. Fariba Jian Motamedi

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Lahiru Chamara Weerasinghe Arachchige

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4492-8946
  4. Amelie Tison

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephen T Bradford

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9508-3894
  6. Jonathan Lefebvre

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Pascal Dolle

    Inserm U1258, UNISTRA CNRS, UMR7104, IGBMC, Illkirch, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Norbert B Ghyselinck

    Inserm U1258, UNISTRA CNRS, UMR7104, IGBMC, Illkirch, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Kay D Wagner

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Andreas Schedl

    Inserm, CNSR, iBV, Université Côte d'Azur, Nice, France
    For correspondence
    Andreas.Schedl@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9380-7396

Funding

Fondation de France (00056856)

  • Andreas Schedl

Fondation ARC pour la Recherche sur le Cancer (SL22020605297)

  • Andreas Schedl

Agence Nationale de la Recherche (ANR-11-LABX-0028-01)

  • Fabio Da Silva
  • Andreas Schedl

Ligue Contre le Cancer (equipe labelisée 2018)

  • Andreas Schedl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal work was conducted according to national and international guidelines and was approved by the local ethics committee (PEA-NCE/2013/88).

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Publication history

  1. Received: March 14, 2021
  2. Accepted: October 7, 2021
  3. Accepted Manuscript published: October 8, 2021 (version 1)

Copyright

© 2021, Da Silva et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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