Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants

Alan Arthur Sneddon, H C Wu, Andrew Farquharson, Ian Grant, John Arthur, D Rotondo, S N Choe, Klaus Wilfried Juergen Wahle

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with a-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. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)57-65
Number of pages9
JournalAtherosclerosis
Volume171
Issue number1
Early online date14 Oct 2003
DOIs
Publication statusPublished - Nov 2003

Keywords

  • HUVEC
  • fatty acids
  • cytokines
  • tumour necrosis factor alpha
  • selenium
  • hydroperoxide glutathione-peroxidase
  • messenger-RNA stability
  • selenium deficiency
  • adhesion molecule-1
  • P-selectin
  • atherosclerosis
  • disease
  • supplementation
  • overexpression
  • lipoprotein

Cite this

Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants. / Sneddon, Alan Arthur; Wu, H C ; Farquharson, Andrew; Grant, Ian; Arthur, John; Rotondo, D ; Choe, S N ; Wahle, Klaus Wilfried Juergen.

In: Atherosclerosis, Vol. 171, No. 1, 11.2003, p. 57-65.

Research output: Contribution to journalArticle

Sneddon, Alan Arthur ; Wu, H C ; Farquharson, Andrew ; Grant, Ian ; Arthur, John ; Rotondo, D ; Choe, S N ; Wahle, Klaus Wilfried Juergen. / Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants. In: Atherosclerosis. 2003 ; Vol. 171, No. 1. pp. 57-65.
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AB - Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with a-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. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

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KW - adhesion molecule-1

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KW - atherosclerosis

KW - disease

KW - supplementation

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