title: Angiotensin II reduces macrophage cholesterol efflux: a role for the AT-1 receptor but not for the ABC1 transporter.
abstract: Impaired cellular cholesterol efflux in cells of the arterial wall is suggested to be involved in the pathogenesis of atherosclerosis. Since angiotensin II (Ang-II) is implicated in the development of atherosclerosis, the aim of the present study was to determine whether Ang-II could affect macrophage cholesterol efflux. Incubation of increasing concentrations of Ang-II (10(-10)-10(-7) M) with mouse peritoneal macrophages that were prelabeled with [3H]cholesterol led to a significant decrease in HDL-induced macrophage cholesterol efflux, by up to 70% compared to control cells incubated without Ang-II. Ang-II specifically increased the plasma membrane unesterified cholesterol content, the substrate for HDL-induced cholesterol efflux. The inhibitory effect of Ang-II on macrophage cholesterol efflux was found to be mediated by the angiotensin II type 1 (AT-1) receptor, since addition of the AT-1 antagonist Losartan completely blocked the inhibitory effect of Ang-II on the macrophage cholesterol efflux. We thus conclude that Ang-II atherogenicity may be related, at least in part, to its inhibitory effect on macrophage cholesterol efflux, thus leading to cellular cholesterol accumulation, the hallmark of early atherogenesis.
authors.affiliation: Lipid Research Laboratory, Rappaport Family Institute for Research in Medical Sciences and Rambam Medical Center, Haifa, Israel.
authors.forename: Marielle
authors.initials: M
authors.lastname: Kaplan
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
authors.forename: Carlos
authors.initials: C
authors.lastname: Knopf
authors.forename: Shlomo
authors.initials: S
authors.lastname: Keidar
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism* / Q000493:pharmacokinetics; D008076:Cholesterol, HDL / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D057911:Angiotensin Receptor Antagonists; D008076:Cholesterol, HDL; D006023:Glycoproteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D002784:Cholesterol; D019808:Losartan