title: Angiotensin AT1 receptor blockers suppress oxidized low-density lipoprotein-derived formation of foam cells.
abstract: Although angiotensin II potently affects blood pressure and fluid balance, it is also involved in deterioration in atherosclerotic cardiovascular disease. Recently, angiotensin AT(1) receptor blockers have been demonstrated to be effective in patients with atherosclerotic disease, but the exact mechanisms of these blockers are still controversial. Atherosclerotic plaques are characterized by cholesterol ester accumulation and acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) expression, which are both parameters of degeneration of macrophage-derived foam cells. We examined the effects of angiotensin AT(1) receptor blockers on the formation of foam cells from macrophages. When macrophages from a human cell line were stimulated with oxidized low-density lipoprotein (oxLDL), the angiotensin AT(1) receptor blockers candesartan and losartan attenuated the intracellular accumulation of cholesterol ester and the increases in mRNA and protein levels of ACAT-1. Moreover, the increase in oxLDL-induced ACAT-1 was reduced by AG1478, an inhibitor of the epidermal growth factor (EGF) receptor. Additionally, oxLDL up-regulated the protein level of heparin-binding EGF-like growth factor (HB-EGF), a ligand of the EGF receptor. Inhibitors of angiotensin-converting enzyme affected neither cholesterol ester accumulation nor the expression of ACAT-1. Although oxLDL itself increased the secretion of angiotensin II, the amount of secreted angiotensin II was insufficient to induce expression of ACAT-1 protein. Thus, we first demonstrated that angiotensin AT(1) receptor blockers suppress ACAT-1 expression and cholesterol ester accumulation through an oxLDL-activated EGF receptor, but it is unclear how oxLDL activates angiotensin AT1 receptor in an angiotensin II-independent manner. The therapeutic mechanism of angiotensin AT(1) receptor blockers for atherosclerosis may be at least partially explained by our present results.
authors.affiliation: Department of Pharmacology, Osaka City University Graduate School of Medicine, Japan. osada@med.osaka-cu.ac.jp
authors.forename: Mayuko
authors.initials: M
authors.lastname: Osada-Oka
authors.forename: Haruna
authors.initials: H
authors.lastname: Kita
authors.forename: Seiko
authors.initials: S
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
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; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D011799:Quinazolines; D013777:Tetrazoles; D014280:Triglycerides; D020032:Tyrphostins; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; C101044:RTKI cpd; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D066246:ErbB Receptors; D019808:Losartan; C081643:candesartan