Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6.
The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10(-7) mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.
Keidar
S
S
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
Heinrich
R
R
Kaplan
M
M
Hayek
T
T
Aviram
M
M
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000378:metabolism*; D007267:Injections; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000276:immunology
D000906:Antibodies; D001057:Apolipoproteins E; D018955:CD36 Antigens; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; D019808:Losartan