Inhibition of adrenergic β1-AR/Gαs signaling promotes cardiomyocyte proliferation in juvenile mice through activation of RhoA-YAP axis
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.
RNA seq data have been deposited to GEO under accession code GSE186099.
Gene expression changes in beta-blocker treated neonatal heartsNCBI Gene Expression Omnibus, GSE186099.
Article and author information
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.
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).
- Enzo R. Porrello, Murdoch Children's Research Institute, Australia
- Received: October 9, 2021
- Preprint posted: October 20, 2021 (view preprint)
- Accepted: December 7, 2022
- Accepted Manuscript published: December 8, 2022 (version 1)
- Version of Record published: December 20, 2022 (version 2)
© 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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