A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

Autor: Nguyen NUN; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Canseco DC; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Xiao F; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Nakada Y; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Li S; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Lam NT; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Muralidhar SA; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Savla JJ; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Hill JA; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Le V; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Zidan KA; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., El-Feky HW; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Wang Z; Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Ahmed MS; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Hubbi ME; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Menendez-Montes I; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Moon J; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Ali SR; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Le V; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Villalobos E; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Mohamed MS; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Elhelaly WM; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Thet S; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Anene-Nzelu CG; Cardiovascular Research Institute, National University of Singapore, Singapore, Singapore.; Genome Institute of Singapore, Singapore, Singapore., Tan WLW; Cardiovascular Research Institute, National University of Singapore, Singapore, Singapore.; Genome Institute of Singapore, Singapore, Singapore., Foo RS; Cardiovascular Research Institute, National University of Singapore, Singapore, Singapore.; Genome Institute of Singapore, Singapore, Singapore., Meng X; The College of Life Sciences, Northwest University, Xi'an, China., Kanchwala M; Eugene McDermott Center for Human Growth and Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Xing C; Eugene McDermott Center for Human Growth and Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Roy J; Department of Biology, Stanford University, Stanford, California, USA., Cyert MS; Department of Biology, Stanford University, Stanford, California, USA., Rothermel BA; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA., Sadek HA; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA. hesham.sadek@utsouthwestern.edu.; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA. hesham.sadek@utsouthwestern.edu.; Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA. hesham.sadek@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Jun; Vol. 582 (7811), pp. 271-276. Date of Electronic Publication: 2020 Apr 22.
DOI: 10.1038/s41586-020-2228-6
Abstrakt: A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes 1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest 3 . Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.
Databáze: MEDLINE
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