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Sci Transl Med. 2019 Oct 9;11(513). pii: eaaw6419. doi: 10.1126/scitranslmed.aaw6419.

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

Author information

1
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.
2
Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
3
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Pediatric Gastroenterology, Hepatology and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
5
Division of Genetics and Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Department of Biology, School of Arts and Sciences, University of Pennsylvania, 301A/B Lynch Laboratory, 433 S University Avenue, Philadelphia, PA 19104, USA.
7
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Division of Cardiothoracic Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
9
Pediatric Cardiothoracic Surgery, UPMC Children's Hospital of Pittsburgh and Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA 15224, USA.
10
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
11
Department of Computational & Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
12
Pittsburgh Center for Evolutionary Biology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
13
Computational Biology Department and Machine Learning Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
14
Rangos Research Center Animal Imaging Core, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
15
Diabetes and Beta Cell Biology Center, Division of Endocrinology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15238, USA.
16
Division of Cardiology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
17
Neonatal-Perinatal Medicine, UPMC Magee-Womens Hospital, Pittsburgh, PA 15213, USA.
18
Division of Pediatric Pathology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
19
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. bernhard.kuhn2@chp.edu.
20
McGowan Institute of Regenerative Medicine, Pittsburgh, PA 15219, USA.
21
Pediatric Institute for Heart Regeneration and Therapeutics, Pittsburgh, PA 15224, USA.

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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