Keidar Shlomo, Heinrich Ronit, Kaplan Marielle, Aviram Michael
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute in the Medical Sciences and Rambam Medical Center, Haifa, Israel.
J Renin Angiotensin Aldosterone Syst. 2002 Mar;3(1):24-30. doi: 10.3317/jraas.2002.004.
Angiotensin II (Ang II) has been shown to accelerate atherogenesis, and the cellular Ang II type 1 (AT(1))-receptor mediates most of Ang II-induced pro-atherogenic effects. In this study we have examined the effect of macrophage oxidative stress on cellular AT(1)-receptor expression. Mouse peritoneal macrophages (MPM) from apolipoprotein-E deficient (E(0)) mice at increasing ages (1 6 months) demonstrated an age-dependent increase in cellular lipid-peroxides (PD) content. In parallel, the AT(1)-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 E(0) mice significantly decreased the MPM PD content and macrophage AT(1)-receptor mRNA expression compared with placebo-treated mice. The role of oxidative stress in the cellular expression of AT(1)-receptors was further demonstrated by manipulation of macrophage glutathione content. Buthionine-sulfoximine, a glutathione synthesis inhibitor, increased MPM PD content and AT(1)-receptor mRNA expression, whereas L-2-oxothiazolidine-4-carboxylic acid, that contributes to glutathione synthesis, reduced macrophage PD and AT(1)-receptor mRNA expression. Incubation of MPM with oxidised low-density lipoproteins (LDL) led to a significant, dose-dependent and time-dependent increase in macrophage AT(1)-receptor mRNA and protein expression, compared with control cells. In contrast, native LDL or acetylated LDL did not significantly affect macrophage AT(1)-receptor mRNA expression. In conclusion, our findings suggest that oxidative stress in macrophages induces AT(1)-receptor expression. This phenomenon can stimulate the interaction of Ang II with macrophages and hence accelerate macrophage foam cell formation and early atherogenesis.
血管紧张素II（Ang II）已被证明可加速动脉粥样硬化的发生，细胞血管紧张素II 1型（AT(1)）受体介导了大部分Ang II诱导的促动脉粥样硬化作用。在本研究中，我们检测了巨噬细胞氧化应激对细胞AT(1)受体表达的影响。来自不同年龄（1至6个月）的载脂蛋白E缺陷（E(0)）小鼠的小鼠腹腔巨噬细胞（MPM）显示，细胞脂质过氧化物（PD）含量呈年龄依赖性增加。同时，与1个月龄小鼠相比，6个月龄小鼠的MPM中AT(1)受体mRNA和蛋白水平分别增加了3.7倍和1.7倍。与安慰剂处理的小鼠相比，给E(0)小鼠补充维生素E可显著降低MPM的PD含量和巨噬细胞AT(1)受体mRNA表达。通过调节巨噬细胞谷胱甘肽含量进一步证明了氧化应激在AT(1)受体细胞表达中的作用。谷胱甘肽合成抑制剂丁硫氨酸亚砜胺增加了MPM的PD含量和AT(1)受体mRNA表达，而有助于谷胱甘肽合成的L-2-氧代噻唑烷-4-羧酸则降低了巨噬细胞的PD和AT(1)受体mRNA表达。与对照细胞相比，用氧化型低密度脂蛋白（LDL）孵育MPM导致巨噬细胞AT(1)受体mRNA和蛋白表达显著、剂量依赖性和时间依赖性增加。相比之下，天然LDL或乙酰化LDL对巨噬细胞AT(1)受体mRNA表达没有显著影响。总之，我们的研究结果表明，巨噬细胞中的氧化应激诱导AT(1)受体表达。这种现象可刺激Ang II与巨噬细胞的相互作用，从而加速巨噬细胞泡沫细胞形成和早期动脉粥样硬化的发生。
