Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins.
Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7) M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin, an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which active phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.
Keidar
S
S
Lipid Research Laboratory, Rambam Medical Center, Bruce Rappaport Technion Faculty of Medicine, Haifa, Israel.
Kaplan
M
M
Hoffman
A
A
Aviram
M
M
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D015227:Lipid Peroxidation / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008315:Malondialdehyde; D051379:Mice; D008807:Mice, Inbred BALB C; D010105:Oxygenases / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism
D008077:Lipoproteins, LDL; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D008315:Malondialdehyde; D010105:Oxygenases; D010740:Phospholipases; D002118:Calcium