Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette Al and nuclear factors (Publication with Expression of Concern)

Objectives: Understanding the mechanisms involved in oxidative stress-induced foam cell formation is of fundamental importance for atherosclerosis. Our aim was to characterize the effects of oxidative stress on key receptors of macrophage cholesterol homeostasis, on the nuclear transcription factors PPAR and LXR regulating their expression, and on macrophage cholesterol handling. Methods and results: The incubation of macrophages derived from the human monocyte cell line THP-1 with iron (100 mu m)/ascorbate (1000 p m) for a period of 4 h induced a strong peroxidation, as demonstrated by the elevation of malondialdehyde (220%, P < 0.001). The production of lipid peroxidation affected cholesterol efflux, which was probably due to decreased ABCA1 gene and protein expression. On the other hand, cholesterol influx remained unchanged as did the mRNA and protein levels of SR-BI and CD36, important protein receptors that participate in cholesterol import. Experiments using RT-PCR showed that the ABCAI modulation was orchestrated by the nuclear receptors LXR alpha, LXR beta, PPAR alpha, and PPAR gamma. Treatment with powerful antioxidants (Trolox and BHT) prevented the adverse effects of iron-ascorbate on cholesterol movement, conceivably supporting the role of oxidative stress. Conclusion: Our results show that oxidative stress can directly be induced in macrophages and concomitantly impairs the expression of receptors involved in cholesterol flux, which could influence foam cell formation and atherosclerosis development. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.