Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants.
Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha-tocopherol to inhibit lipid peroxidation. Peroxidation of lipids has been implicated in a number of pathophysiological processes, including inflammation and atherogenesis. We investigated the relative positive and negative effects of specific polyunsaturated fatty acids (PUFAs) and inflammatory cytokines on the activity and gene expression of the selenium-dependant redox enzyme GPx4. In human umbilical vein endothelial cells (HUVEC), GPx4 mRNA levels and activity were increased optimally by 114 nM selenium (as sodium selenite). Docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA) further increased mRNA levels whereas arachidonic acid (ARA) had no effect; enzyme activity was decreased by DHA, was unaffected by CLA or was increased by ARA. GPx4 protein levels increased with selenium, ARA and DHA addition but not with CLA. Interleukin-1beta (IL-1beta) increased GPx4 mRNA, protein and activity whereas TNFalpha at 1 ng/ml increased activity while at 3 ng/ml it reduced activity and mRNA. Conversely, alpha-tocopherol reduced mRNA levels without affecting activity. These results indicate that lipids, cytokines and antioxidants modulate GPx4 in a complex manner that in the presence of adequate selenium, may favour protection against potentially proatherogenic processes.
Sneddon
Alan A
AA
Lipid and Redox Regulation Group, Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, UK.
Wu
Hsin-Chieh
HC
Farquharson
Andrew
A
Grant
Ian
I
Arthur
John R
JR
Rotondo
Dino
D
Choe
Sun-Nam
SN
Wahle
Klaus W J
KW
D000975:Antioxidants / Q000008:administration & dosage*; D016718:Arachidonic Acid / Q000008:administration & dosage; D016207:Cytokines / Q000008:administration & dosage*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000201:enzymology*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage; D019787:Linoleic Acid / Q000008:administration & dosage; D015227:Lipid Peroxidation / Q000187:drug effects; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018038:Sodium Selenite / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D024502:alpha-Tocopherol / Q000008:administration & dosage
D000975:Antioxidants; D016207:Cytokines; D005231:Fatty Acids, Unsaturated; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019787:Linoleic Acid; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D024502:alpha-Tocopherol; D018038:Sodium Selenite