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

Abstract

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 proatherogenic 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.

Macrophage Polarization by Angiotensin II-Type 1 Receptor Aggravates Renal Injury-Acceleration of Atherosclerosis

“…3–7 The proatherogenic effects of AII and the anti-atherogenic effects of ACEI and ARB have been linked to modulation of macrophage functions, including chemotaxis, intimal recruitment, inflammation, neovascularization, and proteolysis. 3, 4, 8, 9 AII can modulate macrophage-specific functions, as supported by observations that monocyte/macrophages express components of the angiotensin system, including the aongiotensin II type 1 receptor (AT1), and that cellular exposure to AII promotes lipid accumulation, migration and cytokine production. 4, 8, 9 Nonetheless, the specific contribution in vivo of the macrophage AT1 receptor to atherogenesis has been controversial, ranging from little influence observed in some studies 10 to significant proatherogenic effects reported by others, especially in the setting of infusion of exogenous AII.…”

Angiotensin-TGF-β1 Crosstalk in Human Idiopathic Pulmonary Fibrosis:Autocrine Mechanisms in Myofibroblasts and Macrophages

“…Oxidative stress increases the expression of the AT1 receptor in monocytes/macrophages, which can enhance macrophage formation [66]. Moreover, ANGII may induce cellular responses through free radical generation [41], particularly through NAD(P)H complex [67], which mediates the activation of protein kinase B and JAK/STAT signaling.…”

Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species

“…The effects of oxidative stress on AT 1 receptor expression were also studied in macrophages, since Ang II is a proatherogenic molecule and both oxidative stress and AT 1 receptor expression are increased in hypercholesterolaemia [145][146][147]. In mouse peritoneal macrophages (MPMs) harvested from the E 0 mice, an animal model of severe hypercholesterolemia and atherosclerosis caused by apolipoprotein E deficiency, there was an age-dependent increase in lipid peroxide content accompanied by an age-dependent increase in the AT 1 receptor mRNA and protein expression [146]. MPMs obtained from 3.5 months old E 0 mice treated for 6 weeks with the potent antioxidant vitamin E had lower lipid peroxides concentration and reduced AT 1 receptor mRNA expression, compared to MPMs harvested from untreated E 0 mice [146].…”

“…In mouse peritoneal macrophages (MPMs) harvested from the E 0 mice, an animal model of severe hypercholesterolemia and atherosclerosis caused by apolipoprotein E deficiency, there was an age-dependent increase in lipid peroxide content accompanied by an age-dependent increase in the AT 1 receptor mRNA and protein expression [146]. MPMs obtained from 3.5 months old E 0 mice treated for 6 weeks with the potent antioxidant vitamin E had lower lipid peroxides concentration and reduced AT 1 receptor mRNA expression, compared to MPMs harvested from untreated E 0 mice [146]. To further demonstrate the role of oxidative stress in the regulation of macrophage AT 1 receptor, the GSH content was manipulated by the supplementation for 5 weeks with BSO or with L-2-oxothiazolidine-4-carboxylic acid (OTC), a precursor of GSH synthesis.…”