期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 11, 期 513, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw6419
关键词
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资金
- Richard King Mellon Foundation Institute for Pediatric Research (UPMC Children's Hospital of Pittsburgh)
- Transatlantic Network of Excellence grant by Foundation Leducq [15CVD03]
- Children's Cardiomyopathy Foundation
- NIH [R01HL106302]
- Health Research Formula Funds from the Commonwealth of Pennsylvania
- UPMC Children's Hospital of Pittsburgh
- Genomics Discovery Award
- UPP physicians, Vascular Medicine Institute, Aging Institute
- NIH from the Clinical and Translational Sciences Institute (University of Pittsburgh) [UL1TR001857]
- HeartFest
- [U01MH098953]
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 beta-adrenergic receptors (beta-ARs). Inactivation of the beta-AR genes and administration of the beta-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 beta-blockers could be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.
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