© 1996 American Heart Association, Inc.
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Angiotensin II–Modified LDL Is Taken Up by Macrophages Via the Scavenger Receptor, Leading to Cellular Cholesterol Accumulation
From The Lipid Research Laboratory, Rambam Medical Center, Rappaport Institute for Research in the Medical Sciences, The Bruce Rappaport Technion Faculty of Medicine, Haifa, Israel.
Correspondence to Dr Shlomo Keidar, The Lipid Research Laboratory, Rambam Medical Center, Rappaport Institute for Research in the Medical Sciences, The Bruce Rappaport Technion Faculty of Medicine, Haifa 31096, Israel.
Abstract The incidence of myocardial infarction is significantly higher in hypertensive patients with increased plasma concentration of angiotensin (Ang) II. Ang II was shown to bind to LDL in vitro, and in the present study we showed its binding to LDL in vivo. Ang II (10-7 mol/L) was incubated with LDL for 3 hours at 37°C, followed by reseparation of the modified lipoprotein (Ang II–LDL) and its incubation with J-774 A.1 macrophages. Binding of Ang II to LDL significantly increased the lipoprotein protein degradation (by 25%) and its cell association (by 75%) compared with nontreated LDL. Unlike Ang II–LDL, both Ang I–LDL and Ang III–LDL were taken up by macrophages similar to native LDL. The lipid composition and size of Ang II–LDL were similar to those of native LDL, and it was not aggregated. Ang II–LDL was not oxidized, as the contents of malondialdehyde and peroxides were not different from those found in native LDL. On heparin-Sepharose column chromatography, Ang II–LDL was eluted in the void volume, like acetylated LDL (Ac-LDL) and unlike native LDL, which binds to heparin. The cellular degradation of Ang II-125I–labeled LDL by J-774 A.1 macrophages was studied in the presence of a 50-fold excess of nonlabeled native LDL, Ang II–LDL, Ac-LDL, or oxidized LDL (Ox-LDL). Whereas native LDL had no effect on the degradation of Ang II-125I–LDL by the macrophages, Ac-LDL, Ox-LDL, and Ang II–LDL reduced the cellular uptake of the lipoprotein by 77%, 82%, and 87%, respectively. Similarly, fucoidin but not free Ang II reduced macrophage degradation of the labeled Ang II–LDL. We conclude that Ang II can modify LDL to a form that is not oxidized or aggregated but is still taken up at an enhanced rate by macrophages via the scavenger receptor.
Key Words: angiotensin • LDL • macrophages • scavenger receptor
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