Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages.
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.
Keidar
Shlomo
S
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute in the Medical Sciences and Rambam Medical Center, Haifa, Israel. skeidar@ramram.health.gov.il
Heinrich
Ronit
R
Kaplan
Marielle
M
Aviram
Michael
M
D000375:Aging / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015153:Blotting, Western; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014810:Vitamin E / Q000378:metabolism
D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D014810:Vitamin E; D005978:Glutathione