Inhibition of adrenergic β1-AR/Gαs signaling promotes cardiomyocyte proliferation 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 a cardiomyocyte specific β1-adrenergic receptor (β1-AR) blocker (metoprolol) to examine its role in heart maturation and regeneration at the neonatal stage. We found that metoprolol robustly 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 cardiomyocytes of β-blocker treated and Gnas cKO hearts maintained an immature proliferating status even at the young-adult age, and that the loss of Gαs function enhanced the activity of the Hippo-effector YAP, which is associated with immature cardiomyocyte proliferation. Moreover, the increased YAP activity is modulated by RhoA signaling. Our pharmacological and genetic studies reveal a previously unrecognized β1-AR-Gαs-YAP signaling axis for regulating cardiac regeneration. These results suggest that inhibiting β-AR-Gαs signaling promotes the regenerative capacity and extends the cardiac regenerative window in mice by activating YAP-mediated transcriptional programs. Thus, targeting β-AR-Gαs signaling may serve as a novel therapeutic target for the treatment of ischemic heart.