STAT5b is a key effector of NRG-1/ERBB4-mediated myocardial growth.

Autor: Vaparanta K; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Institute of Biomedicine, University of Turku, Turku, Finland., Jokilammi A; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Institute of Biomedicine, University of Turku, Turku, Finland., Paatero I; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Merilahti JA; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Heliste J; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Institute of Biomedicine, University of Turku, Turku, Finland., Hemanthakumar KA; Wihuri Research Institute, Helsinki, Finland.; Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Kivelä R; Wihuri Research Institute, Helsinki, Finland.; Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland., Alitalo K; Wihuri Research Institute, Helsinki, Finland.; Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Taimen P; Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Turku, Finland.; Department of Pathology, Turku University Hospital, Turku, Finland., Elenius K; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Oncology, Turku University Hospital, Turku, Finland.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2023 May 04; Vol. 24 (5), pp. e56689. Date of Electronic Publication: 2023 Apr 03.
DOI: 10.15252/embr.202256689
Abstrakt: The growth factor Neuregulin-1 (NRG-1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate in several in vitro and in vivo models that STAT5b mediates NRG-1/EBBB4-stimulated cardiomyocyte growth. Genetic and chemical disruption of the NRG-1/ERBB4 pathway reduces STAT5b activation and transcription of STAT5b target genes Igf1, Myc, and Cdkn1a in murine cardiomyocytes. Loss of Stat5b also ablates NRG-1-induced cardiomyocyte hypertrophy. Dynamin-2 is shown to control the cell surface localization of ERBB4 and chemical inhibition of Dynamin-2 downregulates STAT5b activation and cardiomyocyte hypertrophy. In zebrafish embryos, Stat5 is activated during NRG-1-induced hyperplastic myocardial growth, and chemical inhibition of the Nrg-1/Erbb4 pathway or Dynamin-2 leads to loss of myocardial growth and Stat5 activation. Moreover, CRISPR/Cas9-mediated knockdown of stat5b results in reduced myocardial growth and cardiac function. Finally, the NRG-1/ERBB4/STAT5b signaling pathway is differentially regulated at mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to control human subjects, consistent with a role of the NRG-1/ERBB4/STAT5b pathway in myocardial growth.
(© 2023 The Authors.)
Databáze: MEDLINE
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