The single-nucleotide polymorphism (GPX4c718t) in the glutathione peroxidase 4 gene influences endothelial cell function: interaction with selenium and fatty acids.
METHODS
Selenium (Se) is incorporated into selenoproteins as selenocysteine, which requires structures in the 3'-untranslated region (3'-UTR) of selenoprotein mRNAs. The functional consequences of a single nucleotide polymorphism (SNP) within the 3'-UTR of the selenoprotein GPX4 gene (GPX4c718t) was assessed in human umbilical vein endothelial cells (HUVECs) and monocytes from human volunteers.


RESULTS
HUVEC and monocytes homozygous for the T- or C-variant of the GPX4c718t SNP were assessed for monocyte-endothelial cell adhesion, expression of VCAM-1 and sensitivity to oxidative challenge. Interaction of the SNP with Se and different PUFA and effects on selenoprotein expression were also investigated. HUVEC and monocytes homozygous for the T-variant showed elevated adhesion levels compared to cells of the C-variant. This effect was modified by Se and PUFA. HUVEC homozygous for the T-variant showed elevated levels of VCAM-1 protein in the presence of arachidonic acid, were more sensitive to oxidative challenge and showed Se-dependant changes in lipid peroxide levels and expression of additional selenoproteins.


CONCLUSIONS
These findings demonstrate functional effects of the GPX4c718t SNP in endothelial cells and may suggest that individuals with the TT genotype have impaired endothelial function and are at greater risk of vascular disease compared to individuals with the CC genotype.
Micronutrients Group, Lifelong Health Division, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
Lynne K
LK
Crosley
Shabina
S
Bashir
Fergus
F
Nicol
John R
JR
Arthur
John E
JE
Hesketh
Alan A
AA
Sneddon
D020413:3' Untranslated Regions; D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D005227:Fatty Acids / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D020641:Polymorphism, Single Nucleotide; D012643:Selenium / Q000378:metabolism / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D020413:3' Untranslated Regions; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human; D019010:Vascular Cell Adhesion Molecule-1; D016718:Arachidonic Acid; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012643:Selenium; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
Endothelial; Glutathione peroxidase 4; Monocyte; Selenium; Single nucleotide polymorphism