PT  - JOURNAL ARTICLE
AU  - Jiani C. Yin
AU  - Mathew J. Platt
AU  - Xixi Tian
AU  - Xue Wu
AU  - Peter H. Backx
AU  - Jeremy A. Simpson
AU  - Toshiyuki Araki
AU  - Benjamin G. Neel
TI  - Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in <em>RAF1</em>-Mutant Noonan Syndrome
AID  - 10.1101/122150
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 122150
4099  - http://biorxiv.org/content/early/2017/03/30/122150.short
4100  - http://biorxiv.org/content/early/2017/03/30/122150.full
AB  - 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, post-natal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo. We conclude that NS cardiomyopathy involves cardiomyocytes, ECs, and fibroblasts, TNF/IL6 signaling components represent potential therapeutic targets, and abnormal EC signaling might contribute to other forms of LVH.