Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome

Yin, J. C.; Platt, M. J.; Tian, X.; Wu, X.; Backx, P. H.; Simpson, J. A.; Araki, T.; Neel, B. G.

doi:10.1101/122150

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bioRxiv · 10.1101/122150

Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome

Yin, J. C.·Platt, M. J.·Tian, X.·Wu, X.·Backx, P. H.·Simpson, J. A.·Araki, T.·Neel, B. G.

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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, 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.

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Yin, J. C., Platt, M. J., Tian, X., Wu, X., Backx, P. H., Simpson, J. A., Araki, T., Neel, B. G.. 2017-03-30. Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome. https://doi.org/10.1101/122150

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