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

Jiani C. Yin, Mathew J. Platt, Xixi Tian, Xue Wu, Peter H. Backx, Jeremy A. Simpson (), Toshiyuki Araki () and Benjamin G. Neel ()
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Jiani C. Yin: University of Toronto
Mathew J. Platt: University of Guelph
Xixi Tian: York University
Xue Wu: University of Toronto
Peter H. Backx: York University
Jeremy A. Simpson: University of Guelph
Toshiyuki Araki: Princess Margaret Cancer Centre, University Health Network
Benjamin G. Neel: University of Toronto

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15518

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