Faculty Collaboration Database

Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment. Sci Transl Med 2019 Oct 09;11(513)

Date

10/11/2019

Pubmed ID

31597755

Pubmed Central ID

PMC8132604

DOI

10.1126/scitranslmed.aaw6419

Scopus ID

2-s2.0-85073111294 (requires institutional sign-in at Scopus site)   68 Citations

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.

Author List

Liu H, Zhang CH, Ammanamanchi N, Suresh S, Lewarchik C, Rao K, Uys GM, Han L, Abrial M, Yimlamai D, Ganapathy B, Guillermier C, Chen N, Khaladkar M, Spaethling J, Eberwine JH, Kim J, Walsh S, Choudhury S, Little K, Francis K, Sharma M, Viegas M, Bais A, Kostka D, Ding J, Bar-Joseph Z, Wu Y, Yechoor V, Moulik M, Johnson J, Weinberg J, Reyes-Múgica M, Steinhauser ML, Kühn B

Author

Lu Han PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adrenergic beta-Antagonists
Animals
Animals, Newborn
Cell Proliferation
Cytokinesis
Humans
Mice
Myocytes, Cardiac
Propranolol
Proto-Oncogene Proteins
Rats
Receptors, Adrenergic, beta