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

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...

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Autores principales: Patella, Francesca, Schug, Zachary T., Persi, Erez, Neilson, Lisa J., Erami, Zahra, Avanzato, Daniele, Maione, Federica, Hernandez-Fernaud, Juan R., Mackay, Gillian, Zheng, Liang, Reid, Steven, Frezza, Christian, Giraudo, Enrico, Fiorio Pla, Alessandra, Anderson, Kurt, Ruppin, Eytan, Gottlieb, Eyal, Zanivan, Sara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Biochemistry and Molecular Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349982/
https://www.ncbi.nlm.nih.gov/pubmed/25573745
http://dx.doi.org/10.1074/mcp.M114.045575
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author Patella, Francesca
Schug, Zachary T.
Persi, Erez
Neilson, Lisa J.
Erami, Zahra
Avanzato, Daniele
Maione, Federica
Hernandez-Fernaud, Juan R.
Mackay, Gillian
Zheng, Liang
Reid, Steven
Frezza, Christian
Giraudo, Enrico
Fiorio Pla, Alessandra
Anderson, Kurt
Ruppin, Eytan
Gottlieb, Eyal
Zanivan, Sara
author_facet Patella, Francesca
Schug, Zachary T.
Persi, Erez
Neilson, Lisa J.
Erami, Zahra
Avanzato, Daniele
Maione, Federica
Hernandez-Fernaud, Juan R.
Mackay, Gillian
Zheng, Liang
Reid, Steven
Frezza, Christian
Giraudo, Enrico
Fiorio Pla, Alessandra
Anderson, Kurt
Ruppin, Eytan
Gottlieb, Eyal
Zanivan, Sara
author_sort Patella, Francesca
collection PubMed
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.
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spelling pubmed-43499822015-03-16 Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability Patella, Francesca Schug, Zachary T. Persi, Erez Neilson, Lisa J. Erami, Zahra Avanzato, Daniele Maione, Federica Hernandez-Fernaud, Juan R. Mackay, Gillian Zheng, Liang Reid, Steven Frezza, Christian Giraudo, Enrico Fiorio Pla, Alessandra Anderson, Kurt Ruppin, Eytan Gottlieb, Eyal Zanivan, Sara Mol Cell Proteomics Research 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. The American Society for Biochemistry and Molecular Biology 2015-03 2015-01-08 /pmc/articles/PMC4349982/ /pubmed/25573745 http://dx.doi.org/10.1074/mcp.M114.045575 Text en © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access.
spellingShingle Research
Patella, Francesca
Schug, Zachary T.
Persi, Erez
Neilson, Lisa J.
Erami, Zahra
Avanzato, Daniele
Maione, Federica
Hernandez-Fernaud, Juan R.
Mackay, Gillian
Zheng, Liang
Reid, Steven
Frezza, Christian
Giraudo, Enrico
Fiorio Pla, Alessandra
Anderson, Kurt
Ruppin, Eytan
Gottlieb, Eyal
Zanivan, Sara
Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title_full Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title_fullStr Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title_full_unstemmed Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title_short Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability
title_sort proteomics-based metabolic modeling reveals that fatty acid oxidation (fao) controls endothelial cell (ec) permeability
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349982/
https://www.ncbi.nlm.nih.gov/pubmed/25573745
http://dx.doi.org/10.1074/mcp.M114.045575
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