title: Role of renin-angiotensin system in activation of macrophages by modified lipoproteins.
abstract: Angiotensin II favors the development of atherosclerosis. Our goal was to determine if foam cell formation increases angiotensin II generation by the endogenous renin-angiotensin system (RAS) and if endogenously produced angiotensin II promotes lipid accumulation in macrophages. Differentiated THP-1 cells were treated with acetylated low-density lipoproteins (ac-LDL), native LDL (n-LDL), or no LDL. Expression of RAS genes was assessed and angiotensin I/II levels were quantified in media and cell lysate. Ac-LDL increased angiotensin I/II levels and the angiotensin II/I ratio in cells and media after foam cell formation. Renin mRNA or activity did not change, but renin blockade completely inhibited the increase in angiotensin II. Angiotensinogen mRNA but not protein level was increased. Angiotensin-converting enzyme (ACE) and cathepsin G mRNA and activities were enhanced by ac-LDL. Inhibition of renin, ACE, or the angiotensin II receptor 1 (AT1-receptor) largely abolished cholesteryl ester formation in cells exposed to ac-LDL and decreased scavenger receptor A (SR-A) and acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT-1) protein levels. Inhibition of renin or the AT1-receptor in cells treated with oxidized LDL also decreased SR-A and ACAT-1 protein and foam cell formation. ac-LDL also increased angiotensin II by human peripheral blood monocyte-derived macrophages, whereas blockade of renin decreased cholesterol ester formation in these macrophages. These findings indicate that, during foam cell formation, angiotensin II generation by the endogenous RAS is stimulated and that endogenously generated angiotensin II is crucial for cholesterol ester accumulation in macrophages exposed to modified LDL.
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;
authors.forename: Naimeh
authors.initials: N
authors.lastname: Rafatian
authors.forename: Ross W
authors.initials: RW
authors.lastname: Milne
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
authors.forename: Stewart C
authors.initials: SC
authors.lastname: Whitman
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013997:Time Factors; D000092502:Renin Inhibitors
chemical_list: D000101:Acetyl-CoA C-Acetyltransferase; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen; D056649:Cathepsin G; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D007703:Peptidyl-Dipeptidase A; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; D051117:Scavenger Receptors, Class A; D000092502:Renin Inhibitors; C544065:AGTR1 protein, human; C032629:acetyl-LDL; C506639:ACAT1 protein, human; C488034:ACE protein, human; C534094:CTSG protein, human
keywords: THP-1 cells; acetylated low-density lipoprotein; angiotensin II; cholesteryl ester; foam cells