Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability

Patella, F. and Schug, Z. T. and Persi, E. and Neilson, L. J. and Erami, Z. and Avanzato, D. and Maione, F. and Hernandez-Fernaud, J. R. and Mackay, G. M. and Zheng, L. and Reid, S. and Frezza, C. and Giraudo, E. and Pla, A. F. and Anderson, K. and Ruppin, E. and Gottlieb, E. and Zanivan, S. (2015) Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability. [Data Collection]

Original publication URL: https://dx.doi.org/10.1074/mcp.M114.045575
Enlighten Publications URI: http://eprints.gla.ac.uk/id/eprint/105618

Collection description

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.

College / School: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Beatson Institute of Cancer Research
Date Deposited: 16 Feb 2016 12:45
Enlighten Publications URL: http://eprints.gla.ac.uk/105618/
URI: http://researchdata.gla.ac.uk/id/eprint/271

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Patella, F. and Schug, Z. T. and Persi, E. and Neilson, L. J. and Erami, Z. and Avanzato, D. and Maione, F. and Hernandez-Fernaud, J. R. and Mackay, G. M. and Zheng, L. and Reid, S. and Frezza, C. and Giraudo, E. and Pla, A. F. and Anderson, K. and Ruppin, E. and Gottlieb, E. and Zanivan, S. (2015); Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability

University of Glasgow

http://researchdata.gla.ac.uk/271

Retrieved: 2017-11-20