Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability

Patella, F. et al. (2015) Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability. Molecular and Cellular Proteomics, 14(3), pp. 621-634. (doi:10.1074/mcp.M114.045575) (PMID:25573745) (PMCID:PMC4349982)

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Abstract

Endothelial cells (ECs) play a key role to maintain the functionality of blood vessels. Altered EC permeability causes severe impairment in vessel stability and is a hallmark of pathologies such as cancer and thrombosis. Integrating label-free quantitative proteomics data into genome-wide metabolic modeling, we built up a model that predicts the metabolic fluxes in ECs when cultured on a tridimensional matrix and organize into a vascular-like network. We discovered how fatty acid oxidation increases when ECs are assembled into a fully formed network that can be disrupted by inhibiting CPT1A, the fatty acid oxidation rate-limiting enzyme. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which are restored by replenishing the tricarboxylic acid cycle. Remarkably, global phosphoproteomic changes measured upon acute CPT1A inhibition pinpointed altered calcium signaling. Indeed, CPT1A inhibition increases intracellular calcium oscillations. Finally, inhibiting CPT1A induces hyperpermeability in vitro and leakage of blood vessel in vivo, which were restored blocking calcium influx or replenishing the tricarboxylic acid cycle. Fatty acid oxidation emerges as central regulator of endothelial functions and blood vessel stability and druggable pathway to control pathological vascular permeability.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zanivan, Dr Sara Rossana and Gottlieb, Professor Eyal and Hernandez, Dr Juan and Anderson, Professor Kurt and Patella, Dr Francesca and Mackay, Dr Gillian and Frezza, Mr Christian and Neilson, Ms Lisa and Schug, Dr Zachary and Erami Rud Majani, Mrs Zahra
Authors: Patella, F., Schug, Z. T., Persi, E., Neilson, L. J., Erami Rud Majani, Z., Avanzato, D., Maione, F., Hernandez, J., Mackay, G., Zheng, L., Reid, S., Frezza, C., Giraudo, E., Fiorio Pla, A., Anderson, K., Ruppin, E., Gottlieb, E., and Zanivan, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular and Cellular Proteomics
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:1535-9476
ISSN (Online):1535-9484
Copyright Holders:Copyright © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Molecular and Cellular Proteomics 14(3):621-634
Publisher Policy:Reproduced under a Creative Commons License
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