Inhibition of beta 1-AR/G alpha s 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. beta-adrenergic receptor (beta-AR) blockade has been shown to improve heart functions in response to injury; however, the underlying mechanisms remain poorly understood. Here, we inhibited beta-AR signaling in the heart using metoprolol, a cardio-selective beta blocker for beta 1-adrenergic receptor (beta 1-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 (G alpha s), a downstream effector of beta-AR. Genome wide transcriptome analysis revealed that the Hippo-effector YAP, which is associated with immature cardiomyocyte proliferation, was upregulated in the cardiomyocytes of beta-blocker treated and Gnas cKO hearts. Moreover, the increased YAP activity is modulated by RhoA signaling. Our pharmacological and genetic studies reveal that beta 1-AR-G alpha s-YAP signaling axis is involved in regulating postnatal cardiomyocyte proliferation. These results suggest that inhibiting beta-AR-G alpha s signaling promotes the regenerative capacity and extends the cardiac regenerative window in juvenile mice by activating YAP-mediated transcriptional programs.