Stimulation of the β-ARs activates Gαs activity leading to an increase in intracellular cAMP levels and the subsequent activation of protein kinase A (PKA), which can result in increased heart rate and contractility Rockman et al., 2002 Molkentin and Dorn, 2001. Beta-adrenergic receptors (β-ARs), members of GPCRs that couple to a stimulatory G protein alpha-subunit (Gαs), are essential components of the sympathetic nervous system Lymperopoulos et al., 2013. The Hippo pathway can be activated by several molecular signals, including G-protein-coupled receptors (GPCRs), cell-cell interactions, and alterations in cytoskeletal dynamics Yu et al., 2012 Wada et al., 2011 Kim et al., 2011. However, it remains unknown what upstream signaling cues regulate the Hippo signaling pathway for cardiac regeneration. Moreover, activation of YAP in adult hearts improves cardiac function and reduces scar formation after myocardial infarction (MI) Xin et al., 2013a Heallen et al., 2013 Leach et al., 2017, suggesting that YAP activation promotes cardiomyocyte regeneration even in the adult mouse heart. Activation of YAP in the embryonic heart, either through the loss of Mst1/2, Sav1, or forced expression of a constitutively active form of YAP, induces cardiomyocyte proliferation and increases heart size Xin et al., 2011 Heallen et al., 2011. It consists of a series of kinases, including MERLIN, MST1/2, and LATS1/2, that phosphorylate the downstream effectors YAP and TAZ, preventing their nuclear translocation and activation of target gene expression Varelas, 2014 Hansen et al., 2015. The evolutionarily conserved Hippo signaling pathway is known as a pivotal regulator of organ size and cell proliferation Zhao et al., 2011 Pan, 2010. In addition, signaling pathways such as Hippo, Neuregulin, ERBB2, Agrin, and thyroid hormone have been shown to regulate cardiac regeneration Hirose et al., 2019 D’Uva et al., 2015 Bassat et al., 2017 Mahmoud et al., 2015 Lin et al., 2014. For instance, the postnatal metabolic shift from glycolysis to fatty acid oxidation or aerobic respiration-mediated oxidative DNA damage can lead to cardiomyocyte cell cycle arrest postnatally Nakada et al., 2017 Kimura et al., 2015 Puente et al., 2014. Changes after birth such as metabolic state, oxygen level, cardiomyocyte structure and maturity, hormones, and polyploidy are among the factors contributing to the loss of the regenerative potential in the heart Hirose et al., 2019 Vivien et al., 2016 Nakada et al., 2017 Kimura et al., 2015 Siedner et al., 2003 Derks and Bergmann, 2020 Puente et al., 2014. Neonatal mouse hearts retain regenerative potential following cardiac injury up to 7 days after birth Porrello et al., 2011 Porrello et al., 2013 Xin et al., 2013b. The capacity to regenerate and repair in response to cardiac injury in the adult mammalian heart is limited. These results suggest that inhibiting β-AR-Gαs signaling promotes the regenerative capacity and extends the cardiac regenerative window in juvenile mice by activating YAP-mediated transcriptional programs. Our pharmacological and genetic studies reveal that β1-AR-Gαs-YAP signaling axis is involved in regulating postnatal cardiomyocyte proliferation. Moreover, the increased YAP activity is modulated by RhoA signaling. Genome wide transcriptome analysis revealed that the Hippo-effector YAP, which is associated with immature cardiomyocyte proliferation, was upregulated in the cardiomyocytes of β-blocker treated and Gnas cKO hearts. 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. We found that metoprolol enhanced cardiomyocyte proliferation and promoted cardiac regeneration post myocardial infarction, resulting in reduced scar formation and improved cardiac function. 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. β-adrenergic receptor (β-AR) blockade has been shown to improve heart functions in response to injury however, the underlying mechanisms remain poorly understood. The regeneration potential of the mammalian heart is incredibly limited, as cardiomyocyte proliferation ceases shortly after birth.
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