Research ArticleCardiology

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

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Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaaw6419
DOI: 10.1126/scitranslmed.aaw6419

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Divide and defend

Surgery can correct tetralogy of Fallot, a form of congenital heart disease; however, patients risk cardiac complications and morbidity as adults. Liu et al. found decreased cardiomyocyte cell division in pediatric patients, suggesting that a reduction in endowment (number of cells) could contribute to adult-onset cardiac dysfunction. In mouse models, inactivating the β-adrenergic receptor (β-AR) improved expression of Ect2 and decreased the number of binucleated cardiomyocytes. Propranolol (β-AR blocker) treatment increased cardiomyocyte proliferation in patient cells and in neonatal mice, which led to improved cardiac function and remodeling after myocardial infarction in adult mice. This study suggests that early-life β-blocker treatment could rescue cell division defects, with potential benefit to long-term cardiac health.

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.

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