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 IT 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 by IL-6.