Oxysterol mixtures, in atheroma-relevant proportions, display synergistic and proapoptotic effects.

Abstract

Apoptotic cells in atheroma lesions may contribute to plaque development and instability. Oxysterols constitute the major toxic component in oxLDL and are present in mixed forms in human atheroma lesions. However, the cellular effects of oxysterols have been mostly studied individually. In the present study, we investigated the cytotoxic effects of 7beta-hydroxycholesterol (7betaOH), 7-ketocholesterol (7keto), 25-hydroxycholesterol (25OH), and 27-hydroxycholesterol (27OH) on U937 monocytic cells, both individually and in atheroma-relevant mixtures mimicking the oxysterol composition reported in human atheroma lesions. Apoptosis and necrosis were studied by examining cell morphology, phosphatidylserine exposure, caspase activation, and the terminal dUTP nick end-labeling technique. Cellular reactive oxygen species and total amount of reduced thiols were measured by using fluorescence probes and 5,5'-dithiobis-(2-nitrobenzoic acid), respectively. We found that 7betaOH and 7keto induced caspase activation, ROS production, cellular thiol depletion, permeabilization of lysosomal and mitochondrial membranes, and cell death. 25OH and 27OH did not cause any of the above alterations, whereas 7betaOH and 7keto exerted synergistic toxic effects. Although single 25OH or 27OH exhibited quenching effects on both 7betaOH- and 7keto-induced cell death, the combination of all four oxysterols in atheroma-relevant proportions was proapoptotic. Our findings indicate that the major oxysterols accumulated in human atheroma are proapoptotic and may contribute to atherosclerotic lesion development.

• Authors: David A Larsson, Sarah Baird, Jerome Diinga Nyhalah, Xi-Ming Yuan, Wei Li
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 41 Issue 6 Pg. 902-10 (Sep 15 2006) ISSN: 0891-5849 [Print] United States
• PMID: 16934673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Steroids
• Caspases

Topics

• Apoptosis (drug effects, physiology)
• Atherosclerosis (metabolism, pathology, physiopathology)
• Caspases (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Humans
• Steroids (metabolism, pharmacology)
• U937 Cells