Tryptophan depletion under conditions that imitate insulin resistance enhances fatty acid oxidation and induces endothelial dysfunction through reactive oxygen species-dependent and independent pathways.
In atherosclerosis-associated pathologic entities characterized by malnutrition and inflammation, L-tryptophan (TRP) levels are low. Insulin resistance is an independent cardiovascular risk factor and induces endothelial dysfunction by increasing fatty acid oxidation. It is also associated with inflammation and low TRP levels. Low TRP levels have been related to worse cardiovascular outcome. This study evaluated the effect of TRP depletion on endothelial dysfunction under conditions that imitate insulin resistance. Fatty acid oxidation, harmful pathways due to increased fatty acid oxidation, and endothelial dysfunction were assessed in primary human aortic endothelial cells cultured under normal glucose, low insulin conditions in the presence or absence of TRP. TRP depletion activated general control non-derepressible 2 kinase and inhibited aryl hydrocarbon receptor. It increased fatty acid oxidation by increasing expression and activity of carnitine palmitoyltransferase 1. Elevated fatty acid oxidation increased the formation of reactive oxygen species (ROS) triggering the polyol and hexosamine pathways, and enhancing protein kinase C activity and methylglyoxal production. TRP absence inhibited nitric oxide synthase activity in a ROS-dependent way, whereas it increased the expression of ICAM-1 and VCAM-1 in a ROS independent and possibly p53-dependent manner. Thus, TRP depletion, an amino acid whose low levels have been related to worse cardiovascular outcome and to inflammatory atherosclerosis-associated pathologic entities, under conditions that imitate insulin resistance enhances fatty acid oxidation and induces endothelial dysfunction through ROS-dependent and independent pathways. These findings may offer new insights at the molecular mechanisms involved in accelerated atherosclerosis that frequently accompanies malnutrition and inflammation.
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece. teleftheriadis@yahoo.com.
Theodoros
http://orcid.org/0000-0001-9302-1633
T
Eleftheriadis
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
Georgios
G
Pissas
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
Maria
M
Sounidaki
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
Georgia
G
Antoniadi
Department of Interventional Radiology, Medical School, University of Thessaly, Larissa, Greece.
Christos
C
Rountas
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
Vassilios
V
Liakopoulos
Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110, Larissa, Greece.
Loannis
L
Stefanidis
D001011:Aorta / Q000166:cytology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005227:Fatty Acids; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D014364:Tryptophan / Q000172:deficiency*
D005227:Fatty Acids; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan
Atherosclerosis; Endothelial dysfunction; Fatty acid oxidation; Inflammation; Insulin resistance; ROS; Tryptophan depletion