Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment
Year: 2019
Type: article
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.
Source: Science Translational Medicine
Authors: 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, Bernhard Kühn
Institutions: University of Pittsburgh, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Richard King Mellon Foundation, Boston Children's Hospital, Harvard University, Brigham and Women's Hospital, University of Pennsylvania, University of North Carolina at Chapel Hill, Carnegie Mellon University, Magee-Womens Hospital, McGowan Institute for Regenerative Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Andrew W. Mellon Foundation, Richard King Mellon Foundation, University of Pennsylvania, University of Pittsburgh, Children's Cardiomyopathy Foundation, University College London, Fondation Leducq, Nagaoka University of Technology, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Cancer Institute, National Center for Advancing Translational Sciences, Children's Hospital of Pittsburgh
OpenAlex ID: W2980098439