Losartan inhibits cellular uptake of oxidized LDL by monocyte-macrophages from hypercholesterolemic patients.
Angiotensin II (Ang II) and oxidized LDL (Ox-LDL) are risk factors for atherosclerosis, and both of them contribute to macrophage cholesterol accumulation, the hallmark of early atherosclerosis. As Ang II was shown to increase macrophage uptake of Ox-LDL, we investigated the effect of losartan, an Ang II receptor antagonist with antiatherogenic properties, on the cellular uptake of Ox-LDL by human monocyte-derived macrophages (HMDM) from hypercholesterolemic patients. Eight normotensive hypercholesterolemic patients were treated with losartan (50 mg/day) for a period of 4 weeks. Losartan therapy did not significantly affect the degradation of native LDL by the patients' HMDM. However, losartan therapy significantly reduced HMDM uptake of Ox-LDL as shown by a 78% reduction in Ox-LDL cell-association and a 21% reduction in Ox-LDL degradation. CD36 (an Ox-LDL receptor) mRNA expression in HMDM obtained after losartan treatment was decreased by 54% compared to HMDM obtained before treatment. The ability of losartan to inhibit HMDM CD36 mRNA expression and, hence, Ox-LDL uptake and macrophage foam cell formation is probably related to the blockage of Ang II binding to the cell surface and thus to the prevention of Ang II atherogenic effects.
Hayek
T
T
Lipid Research Laboratory, Technion Faculty of Medicine, Haifa, Israel.
Aviram
M
M
Heinrich
R
R
Sakhnini
E
E
Keidar
S
S
D000804:Angiotensin II / Q000096:biosynthesis; D057911:Angiotensin Receptor Antagonists; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D001693:Biological Transport, Active / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; D019808:Losartan