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

• DOI: 10.1038/ncomms15518
• Publication Date: 2017-05-26T10:21:08Z
• Authors: Jiani C. Yin; Mathew J. Platt; Xixi Tian; Xue Wu; Peter H. Backx; Jeremy A. Simpson; Toshiyuki Araki; Benjamin G. Neel
• Keywords: Pressure overload; Contractility

Abstract Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and characterized craniofacial, growth, cognitive cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which reproduced Raf1 L613V/+ knock-in mice. Here, using inducible L613V expression, we show that LVH results from the interplay of cell types. Cardiomyocyte enhances Ca 2+ sensitivity contractility without causing hypertrophy. expression cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) causes affecting contractility. Co-culture neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy -expressing ECs drives cardiomyocyte vitro . Furthermore, postnatal TNF inhibition normalizes increased wall thickness vivo We conclude NS-cardiomyopathy involves cardiomyocytes, fibroblasts, TNF/IL6 signalling components represent potential therapeutic targets, abnormal EC might contribute to other forms LVH.