Inhibition of adrenergic β1-AR/Gαs signaling promotes cardiomyocyte proliferation in juvenile mice through activation of RhoA-YAP axis

  1. Masahide Sakabe
  2. Michael Thompson
  3. Nong Chen
  4. Mark Verba
  5. Aishlin Hassan
  6. Richard Lu
  7. Mei Xin  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States

Abstract

The regeneration potential of the mammalian heart is incredibly limited, as cardiomyocyte proliferation ceases shortly after birth. β-adrenergic receptor (β-AR) blockade has been shown to improve heart functions in response to injury; however, the underlying mechanisms remain poorly understood. Here we inhibited β-AR signaling in the heart using metoprolol, a cardio-selective β blocker for β1-adrenergic receptor (β1-AR) to examine its role in heart maturation and regeneration in postnatal mice. We found that metoprolol enhanced cardiomyocyte proliferation and promoted cardiac regeneration post myocardial infarction, resulting in reduced scar formation and improved cardiac function. Moreover, the increased cardiomyocyte proliferation was also induced by the genetic deletion of Gnas, the gene encoding G protein alpha subunit (Gαs), a downstream effector of β-AR. Genome wide transcriptome analysis revealed that the Hippo-effector YAP, which is associated with immature cardiomyocyte proliferation, was upregulated in the cardiomyocytes of b-blocker treated and Gnas cKO hearts. Moreover, the increased YAP activity is modulated by RhoA signaling. Our pharmacological and genetic studies reveal that b1-AR-Gas-YAP signaling axis is involved in regulating postnatal cardiomyocyte proliferation. These results suggest that inhibiting b-AR-Gas signaling promotes the regenerative capacity and extends the cardiac regenerative window in juvenile mice by activating YAP-mediated transcriptional programs.

Data availability

RNA seq data have been deposited to GEO under accession code GSE186099.

The following data sets were generated

Article and author information

Author details

  1. Masahide Sakabe

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0851-296X
  2. Michael Thompson

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nong Chen

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Mark Verba

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Aishlin Hassan

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Richard Lu

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mei Xin

    Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    mei.xin@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5732-7501

Funding

National Institutes of Health (HL-132211)

  • Mei Xin

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

Reviewing Editor

  1. Enzo R. Porrello, Murdoch Children's Research Institute, Australia

Ethics

Animal experimentation: All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of Cincinnati Children's Hospital Medical Center (IACUC 2019-0086).

Version history

  1. Received: October 9, 2021
  2. Preprint posted: October 20, 2021 (view preprint)
  3. Accepted: December 7, 2022
  4. Accepted Manuscript published: December 8, 2022 (version 1)
  5. Version of Record published: December 20, 2022 (version 2)

Copyright

© 2022, Sakabe 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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  1. Masahide Sakabe
  2. Michael Thompson
  3. Nong Chen
  4. Mark Verba
  5. Aishlin Hassan
  6. Richard Lu
  7. Mei Xin
(2022)
Inhibition of adrenergic β1-AR/Gαs signaling promotes cardiomyocyte proliferation in juvenile mice through activation of RhoA-YAP axis
eLife 11:e74576.
https://doi.org/10.7554/eLife.74576

Share this article

https://doi.org/10.7554/eLife.74576

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