Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette A1 and nuclear factors

doi:10.1016/j.cardiores.2006.08.024

Cardiovascular Research 2006 72(3):473-482; doi:10.1016/j.cardiores.2006.08.024

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Oxidative stress influences cholesterol efflux in THP-1 macrophages: Role of ATP-binding cassette A1 and nuclear factors

Valérie Marcil^a^,b, Edgard Delvin^a^,c, Alain Théophile Sané^a^,b, André Tremblay^a^,d and Emile Levy^a^,b^,*

^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 oxidativestress-induced foam cell formation is of fundamental importancefor atherosclerosis. Our aim was to characterize the effectsof oxidative stress on key receptors of macrophage cholesterolhomeostasis, on the nuclear transcription factors PPAR and LXRregulating their expression, and on macrophage cholesterol handling.

Methods and results: The incubation of macrophages derived fromthe human monocyte cell line THP-1 with iron (100 µm)/ascorbate(1000 µm) for a period of 4 h induced a strongperoxidation, as demonstrated by the elevation of malondialdehyde(220%, P<0.001). The production of lipid peroxidation affectedcholesterol efflux, which was probably due to decreased ABCAIgene and protein expression. On the other hand, cholesterolinflux remained unchanged as did the mRNA and protein levelsof SR-BI and CD36, important protein receptors that participatein cholesterol import. Experiments using RT-PCR showed thatthe ABCAI modulation was orchestrated by the nuclear receptorsLXR ${alpha}$ , LXRβ, PPAR ${alpha}$ , and PPAR ${gamma}$ . Treatment with powerful antioxidants(Trolox and BHT) prevented the adverse effects of iron-ascorbateon cholesterol movement, conceivably supporting the role ofoxidative stress.

Conclusion: Our results show that oxidative stress can directlybe induced in macrophages and concomitantly impairs the expressionof receptors involved in cholesterol flux, which could influencefoam cell formation and atherosclerosis development.

KEYWORDS ABCA1; SR-BI; CD36; PPAR; LXR; Macrophage; Oxidative stress

This paper was supported by research grants from the CanadianInstitutes of Health Research (CIHR).

Time for primary review 23 days

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