Suppression of atherogenesis by overexpression of glutathione peroxidase-4 in apolipoprotein E-deficient mice

Zhong Mao Guo, Qitao Ran, L. Jackson Roberts, Lichun Zhou, Arlan Richardson, Chakradhari Sharan, Dong Fan Wu, Hong Yang

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Accumulation of oxidized lipids in the arterial wall contributes to atherosclerosis. Glutathione peroxidase-4 (GPx4) is a hydroperoxide scavenger that removes oxidative modifications from lipids such as free fatty acids, cholesterols, and phospholipids. Here, we set out to assess the effects of GPx4 overexpression on atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. The results revealed that atherosclerotic lesions in the aortic tree and aortic sinus of ApoE-/- mice overexpressing GPx4 (hGPx4Tg/ApoE-/-) were significantly smaller than those of ApoE-/- control mice. GPx4 overexpression also diminished signs of advanced lesions in the aortic sinus, as seen by a decreased occurrence of fibrous caps and acellular areas among hGPx4Tg/ApoE-/- animals. This delay of atherosclerosis in hGPx4Tg/ApoE-/- mice correlated with reduced aortic F2-isoprostane levels (R2 = 0.75, p < 0.01). In addition, overexpression of GPx4 lessened atherogenic events induced by the oxidized lipids lysophosphatidylcholine and 7-ketocholesterol, including upregulated expression of adhesion molecules in endothelial cells and adhesion of monocytes to endothelial cells, as well as endothelial necrosis and apoptosis. These results suggest that overexpression of GPx4 inhibits the development of atherosclerosis by decreasing lipid peroxidation and inhibiting the sensitivity of vascular cells to oxidized lipids.

Original languageEnglish (US)
Pages (from-to)343-352
Number of pages10
JournalFree Radical Biology and Medicine
Volume44
Issue number3
DOIs
StatePublished - Feb 1 2008

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Keywords

  • Apoptosis
  • Atherosclerosis
  • Free radicals
  • Glutathione peroxidase-4
  • Lipid peroxidation
  • Monocyte adhesion
  • Necrosis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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