REACTIVE OXYGEN SPECIES REGULATE MACROPHAGE SCAVENGER RECEPTOR-TYPE-I, BUT NOT TYPE-II, IN THE HUMAN MONOCYTIC CELL-LINE THP-1

The uptake of modified low density lipoprotein via the macrophage scav enger receptor (MSR) results in the formation of lipid-laden foam cell s during atherosclerosis. Because increased oxidative stress has been implicated in the pathogenesis of atherosclerosis, the role of reactiv e oxygen species on the activity and expression of MSR was investigate d. The uptake of acetylated low density lipoprotein and the levels of MSR-I mRNA were inhibited by treatment with the oxygen radical scaveng ers 2,2,6,6-tetramethylpiperidine-N-oxyl, dimethylthiourea or sodium b enzoate, or the iron chelator deferoxamine. Dimethylthiourea or benzoa te also decreased the levels of MSR-I mRNA in the presence of the tran scription inhibitor actinomycin D. These results indicate that hydroxy l radicals produced from superoxide anions and hydrogen peroxide in th e presence of free iron, contribute to an increased MSR activity by st abilizing MSR-I mRNA. Several sources of reactive oxygen species are i nvolved as inhibition of MSR activity and levels of MSR-I mRNA occurre d in the presence of rotenone, a mitochondrial complex I inhibitor, or acetovanillone, a NADPH oxidase inhibitor. The (oxidative) stress res ponsive nuclear factor kappa B is not involved as inhibitors of its ac tivation remained without significant inhibition. In contrast to MSR-I , the levels of MSR-II mRNA, which is formed by alternative splicing o f the same gene transcript, were largely unaffected by the inhibitors of reactive oxygen species formation and activity. The present results suggest that oxidant stress contributes to an increased activity of M SR by stabilizing MSR-I mRNA.