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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Coculture Techniques
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Fibrosis
  • Gene Knock-In Techniques
  • Humans
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / pathology*
  • Interleukin-6 / metabolism*
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Myocardium / cytology
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Noonan Syndrome / drug therapy
  • Noonan Syndrome / genetics
  • Noonan Syndrome / pathology*
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-raf / genetics*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Cytokines
  • IL6 protein, human
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human