• Sci Transl Med · Oct 2019

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

    • Honghai Liu, Cheng-Hai Zhang, Niyatie Ammanamanchi, Sangita Suresh, Christopher Lewarchik, Krithika Rao, Gerrida M Uys, Lu Han, Maryline Abrial, Dean Yimlamai, Balakrishnan Ganapathy, Christelle Guillermier, Nathalie Chen, Mugdha Khaladkar, Jennifer Spaethling, James H Eberwine, Junhyong Kim, Stuart Walsh, Sangita Choudhury, Kathryn Little, Kimberly Francis, Mahesh Sharma, Melita Viegas, Abha Bais, Dennis Kostka, Jun Ding, Ziv Bar-Joseph, Yijen Wu, Vijay Yechoor, Mousumi Moulik, Jennifer Johnson, Jacqueline Weinberg, Miguel Reyes-Múgica, Matthew L Steinhauser, and Bernhard Kühn.
    • Richard King Mellon Foundation Institute for Pediatric Research and Division of Cardiology, UPMC Children's Hospital of Pittsburgh and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
    • Sci Transl Med. 2019 Oct 9; 11 (513).

    AbstractOne 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.Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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