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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Francesca Patella
  • Zachary T. Schug
  • Erez Persi
  • Lisa J. Neilson
  • Zahra Erami
  • Daniele Avanzato
  • Federica Maione
  • Juan R. Hernandez-Fernaud
  • Gillian Mackay
  • Liang Zheng
  • Steven Reid
  • Christian Frezza
  • Enrico Giraudo
  • Alessandra Fiorio Pla
  • Kurt Anderson
  • Eytan Ruppin
  • Eyal Gottlieb
  • Sara Zanivan
Externa organisationer
  • Beatson Institute for Cancer Research
  • Tel-Aviv University
  • Citta' della Salute e della Scienza Hospital-University of Turin
  • Institute for Cancer Research and Treatment, Candiolo
  • MRC Cancer Unit
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)621-634
TidskriftMolecular and Cellular Proteomics
Volym14
Utgåva nummer3
StatusPublished - 2015 mar 1
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa