TY - JOUR
T1 - Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis
AU - Kalucka, Joanna
AU - Bierhansl, Laura
AU - Conchinha, Nadine Vasconcelos
AU - Missiaen, Rindert
AU - Elia, Ilaria
AU - Brüning, Ulrike
AU - Scheinok, Samantha
AU - Treps, Lucas
AU - Cantelmo, Anna Rita
AU - Dubois, Charlotte
AU - de Zeeuw, Pauline
AU - Goveia, Jermaine
AU - Zecchin, Annalisa
AU - Taverna, Federico
AU - Morales-Rodriguez, Francisco
AU - Brajic, Aleksandra
AU - Conradi, Lena-Christin
AU - Schoors, Sandra
AU - Harjes, Ulrike
AU - Vriens, Kim
AU - Pilz, Gregor-Alexander
AU - Chen, Rongyuan
AU - Cubbon, Richard
AU - Thienpont, Bernard
AU - Cruys, Bert
AU - Wong, Brian W
AU - Ghesquière, Bart
AU - Dewerchin, Mieke
AU - De Bock, Katrien
AU - Sagaert, Xavier
AU - Jessberger, Sebastian
AU - Jones, Elizabeth A V
AU - Gallez, Bernard
AU - Lambrechts, Diether
AU - Mazzone, Massimiliano
AU - Eelen, Guy
AU - Li, Xuri
AU - Fendt, Sarah-Maria
AU - Carmeliet, Peter
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2018/12/4
Y1 - 2018/12/4
N2 - Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
AB - Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1AΔEC mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1AΔEC mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1AΔEC mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
KW - Animals
KW - Carnitine O-Palmitoyltransferase/metabolism
KW - Cell Proliferation
KW - Energy Metabolism
KW - Fatty Acids/metabolism
KW - HEK293 Cells
KW - Homeostasis
KW - Human Umbilical Vein Endothelial Cells/metabolism
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - NADP/metabolism
KW - Oxidation-Reduction
KW - Oxidative Stress
KW - Receptor, Notch1/metabolism
U2 - 10.1016/j.cmet.2018.07.016
DO - 10.1016/j.cmet.2018.07.016
M3 - Article
C2 - 30146488
SN - 1550-4131
VL - 28
SP - 881-894.e13
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -