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Nat Commun. 2017 May 26;8:15518. doi: 10.1038/ncomms15518.

Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome.

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7.
3
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA.
4
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
5
Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.

Abstract

Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1L613V/+ knock-in mice. Here, using inducible Raf1L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1L613V enhances Ca2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy in Raf1L613V-expressing ECs that drives cardiomyocyte hypertrophy in vitro. Furthermore, postnatal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo. We conclude that NS-cardiomyopathy involves cardiomyocytes, ECs and fibroblasts, TNF/IL6 signalling components represent potential therapeutic targets, and abnormal EC signalling might contribute to other forms of LVH.

PMID:
28548091
PMCID:
PMC5458545
DOI:
10.1038/ncomms15518
[Indexed for MEDLINE]
Free PMC Article

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