Angiotensin II reduces macrophage cholesterol efflux: a role for the AT-1 receptor but not for the ABC1 transporter.
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.
Kaplan
Marielle
M
Lipid Research Laboratory, Rappaport Family Institute for Research in Medical Sciences and Rambam Medical Center, Haifa, Israel.
Aviram
Michael
M
Knopf
Carlos
C
Keidar
Shlomo
S
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*
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