Angiotensin II (Ang II) has been shown to accelerate atherogenesis, and the cellular Ang II type 1 (AT1) -receptor mediates most of Ang II-induced proatherogenic effects. In this study we have examined the effect of macrophage oxidative stress on cellular AT1-receptor expression.
Mouse peritoneal macrophages (MPM) from apolipoprotein-E deficient (E0) mice at increasing ages (1—6 months) demonstrated an age-dependent increase in cellular lipid-peroxides (PD) content. In parallel, the AT1-receptor mRNA and protein levels both increased by up to 3.7-fold and 1.7-fold, respectively, in MPM from 6-month old mice compared with 1-month old mice. Vitamin E supplementation to E0 mice significantly decreased the MPM PD content and macrophage AT1-receptor mRNA expression compared with placebo-treated mice. The role of oxidative stress in the cellular expression of AT1-receptors was further demonstrated by manipulation of macrophage glutathione content. Buthionine-sulfoximine, a glutathione synthesis inhibitor, increased MPM PD content and AT1receptor mRNA expression, whereas L-2-oxothiazolidine-4-carboxylic acid, that contributes to glutathione synthesis, reduced macrophage PD and AT1receptor mRNA expression. Incubation of MPM with oxidised low-density lipoproteins (LDL) led to a significant, dose-dependent and time-dependent increase in macrophage AT1-receptor mRNA and protein expression, compared with control cells. In contrast, native LDL or acetylated LDL did not significantly affect macrophage AT1-receptor mRNA expression.
In conclusion, our findings suggest that oxidative stress in macrophages induces AT1-receptor expression. This phenomenon can stimulate the interaction of Ang II with macrophages and hence accelerate macrophage foam cell formation and early atherogenesis.
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