Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

Abstract

One million patients with congenital heart disease (CHD) live in the United States. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. Here, analysis of heart tissue from an infant with tetralogy of Fallot with pulmonary stenosis (ToF/PS) labeled with isotope-tagged thymidine demonstrated that cardiomyocyte cytokinesis failure is increased in this common form of CHD. We used single-cell transcriptional profiling to discover that the underlying mechanism of cytokinesis failure is repression of the cytokinesis gene ECT2, downstream of β-adrenergic receptors (β-ARs). Inactivation of the β-AR genes and administration of the β-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the number of cardiomyocytes (endowment) and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes in vitro. These results suggest that β-blockers could be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies

“…Mlc2v cre :Ect2 flox/flox mutants had an increase in the mean ratio of BiNucs to MoNucs at P3 of 0.901 ± 0.08 compared to 0.339 ± 0.02 in control mice ( Figures 7C and 7D). This result agrees with recent work by Liu et al (2019), which also showed that the loss of Ect2 results in an increase in BiNucs during the neonatal period and that increased expression of Ect2 leads to increased MoNucs. qPCR revealed a significant decrease in the expression of E2f target genes in Mlc2v cre : Ect2 flox/flox mutants compared to controls, but no significant change in genes that are not E2f targets ( Figure 7E).…”

Myocardial Protection with Beta Blocker Treatment in Infants with Heart Failure Due to Congenital Heart Defects and Duchenne Muscular Dystrophy

“…In conclusion, the recently published data about the impact of propranolol on increased cytokinesis failure in congenital heart disease from H. Liu et al [1] together with our data who show myocardial protection by the decrease of cTnT after propranolol or carvedilol treatment are very important to increase the acceptance of early beta blocker therapy in infants with heart failure and other infants who suffer from early life stress to improve longtime cardiovascular health.…”

“…Recently, H. Liu et al showed that treatment with non-selective beta blockers early after birth might rescue cytokinesis defects in infants with congenital heart defects and prevent heart dysfunction in adulthood in a mouse model [1].…”

Adrenergic Signaling in Circadian Control of Immunity

“…Signaling through adrenergic receptors reportedly modulates various cellular functions or properties, including (but not limited to) cell cycle and proliferation ( 91 , 92 ), migration ( 93 ), and cytokine ( 94 ) and antibody ( 95 ) production. Although historically, signaling through β-ARs has often been associated with anti-inflammatory outcomes, in more recent years, the ability of β-ARs to mediate context-dependent, pro- and anti-inflammatory effects has become more widely appreciated ( 29 , 94 , 96 ).…”