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Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages

The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel, skeidar@ rambam.health.gov.il

Ronit Heinrich

The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel

Marielle Kaplan

The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel

Michael Aviram

The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel

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.

Key Words: angiotensin II • lipid peroxidation • macrophages • atherosclerosis

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 3, No. 1, 24-30 (2002)
DOI: 10.3317/jraas.2002.004


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