Copyright © 2006, European Society of Cardiology
Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette A1 and nuclear factors
aCentre de Recherche, CHU-Sainte-Justine, Université de Montréal, 3175, Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5
bDepartment of Nutrition, Université de Montréal, 3175, Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5
cDepartment of Biochemistry, Université de Montréal, 3175, Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5
dDepartment of Obstetrics and Gynecology, Université de Montréal, 3175, Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5
* Corresponding author. Tel.: +1 514 345 4626; fax: +1 514 345 4999. Email address: emile.levy{at}recherche-ste-justine.qc
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 µm)/ascorbate (1000 µm) 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 ABCAI 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
, LXRβ, PPAR, and PPAR
. 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.
KEYWORDS ABCA1; SR-BI; CD36; PPAR; LXR; Macrophage; Oxidative stress
This paper was supported by research grants from the Canadian Institutes of Health Research (CIHR).
Time for primary review 23 days
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