Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity

Payumo, Alexander Y.; Chen, Xi; Hirose, Kentaro; Chen, Xiaoxin; Hoang, Alison; Khyeam, Sheamin; Yu, Hongyao; Wang, Jiajia; Chen, Qing; Powers, Nevan; Chen, Li; Bigley, Rachel B.; Lovas, Jonathan; Hu, Guang; Huang, Guo N.

doi:10.1161/circulationaha.121.054846

Cited by 21 publications

(15 citation statements)

References 5 publications

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“…When the heart was injured at P7, we show that both pharmacological and genetic inhibition of β1-adrenergic/Gαs-protein reactivate cardiomyocyte proliferation programs and heart regeneration by activating Hippo-YAP signaling, suggesting that β1-adrenergic/Gαs-YAP signaling contributes to extend the cardiac regeneration window at the juvenile stage. At the young-adult age, combination treatment with α/β-blocker and thyroid hormone inhibitor, but not β-blocker itself, is required to enhance cardiomyocyte regeneration after MI surgery Payumo et al, 2021 , suggesting that additional molecules might be needed to promote adult cardiac regeneration. Further investigation is needed to elucidate the molecular mechanism of how different pathways are involved in promoting adult heart regeneration.…”

Section: Discussionmentioning

confidence: 99%

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

Sakabe

Thompson

Chen

et al. 2022

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

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

Sakabe

Thompson

Chen

et al. 2022

eLife

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“…Recent data from our lab demonstrate that pharmacological inhibition of thyroid hormone signaling with propylthiouracil prevents the acquisition of homeothermy. This is further repressed when combined with adrenergic receptor inhibition, suggesting pathway interactions between thyroid and adrenergic receptor signaling (Payumo et al 2021). Importantly, combinatorial blockade of thyroid hormone and adrenergic signaling after birth dramatically increased cardiomyocyte cell cycle entry by 8-fold, abundance of diploid mononucleated cardiomyocytes by 11-fold and enabled a robust cardiac regenerative response to myocardial infarction in P14 mice.…”

Section: Thermogenesis and Heart Regenerative Potentialmentioning

confidence: 99%

Thyroid hormone-dependent regulation of metabolism and heart regeneration

Ross

Omengan

Huang

et al. 2022

Journal of Endocrinology

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While adult zebrafish and newborn mice possess a robust capacity to regenerate their hearts, this ability is generally lost in adult mammals. The logic behind the diversity of cardiac regenerative capacity across the animal kingdom is not well understood. We have recently reported that animal metabolism is inversely correlated to the abundance of mononucleated diploid cardiomyocytes in the heart, which retain proliferative and regenerative potential. Thyroid hormones are classical regulators of animal metabolism, mitochondrial function, and thermogenesis and a growing body of scientific evidence demonstrates that these hormonal regulators also have direct effects on cardiomyocyte proliferation and maturation. We propose that thyroid hormones dually control animal metabolism and cardiac regenerative potential through distinct mechanisms, which may represent an evolutionary tradeoff for the acquisition of endothermy and loss of heart regenerative capacity. In this review, we describe the effects of thyroid hormones on animal metabolism and cardiomyocyte regeneration, and highlight recent reports linking the loss of mammalian cardiac regenerative capacity to metabolic shifts occurring after birth.

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“…Investigating these differential responses to cardiac injury provides prospects to pinpoint targets in cardiac regeneration. Several factors have been proposed to explain the differences in regenerative capacity, including polyploidisation [ 15 ], endothermy [ 16 , 17 ], oxygen-rich environments [ 18 ], and the immune response [ 19 , 20 ]. Communication between the different cell types composing the heart through both direct physical contact and paracrine signalling can also affect the reparative response ( Figure 1 ).…”

Section: The Need For Heart Regenerationmentioning

confidence: 99%

Cardiac regeneration following myocardial infarction: the need for regeneration and a review of cardiac stromal cell populations used for transplantation

Alonaizan

Carr

2022

Biochemical Society Transactions

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Myocardial infarction is a leading cause of death globally due to the inability of the adult human heart to regenerate after injury. Cell therapy using cardiac-derived progenitor populations emerged about two decades ago with the aim of replacing cells lost after ischaemic injury. Despite early promise from rodent studies, administration of these populations has not translated to the clinic. We will discuss the need for cardiac regeneration and review the debate surrounding how cardiac progenitor populations exert a therapeutic effect following transplantation into the heart, including their ability to form de novo cardiomyocytes and the release of paracrine factors. We will also discuss limitations hindering the cell therapy field, which include the challenges of performing cell-based clinical trials and the low retention of administered cells, and how future research may overcome them.

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Adrenergic-Thyroid Hormone Interactions Drive Postnatal Thermogenesis and Loss of Mammalian Heart Regenerative Capacity

Cited by 21 publications

References 5 publications

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

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

Thyroid hormone-dependent regulation of metabolism and heart regeneration

Cardiac regeneration following myocardial infarction: the need for regeneration and a review of cardiac stromal cell populations used for transplantation

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