Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages.
Angiotensin II (Ang II) is known to accelerate the progression of macrophage-driven atherosclerotic lesions. Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets, and promotes foam cell formation in atherosclerotic lesions. The present study explored the effect of Ang II on ACAT1 expression as a molecular mechanism of foam cell formation in primary cultured human monocyte-macrophages. Ang II significantly increased ACAT1 protein expression in a time- or concentration-dependent manner. Application of an Ang II type 1 (AT(1)) receptor agonist (L162313), but not an Ang II type 2 (AT(2)) receptor agonist (CGP42112A), mimicked the effects of Ang II treatment in inducing ACAT1 protein expression. ACAT activity and ACAT1 mRNA levels were also significantly increased by Ang II. Two-fold increases in ACAT1 protein expression and ACAT activity with Ang II treatment were completely inhibited by AT(1) receptor antagonists (candesartan, [Sar(1),Ile(8)]-Ang II), but not by an AT(2) receptor antagonist (PD123319). Treatment with a G-protein inactivator (GDP-beta-S), a c-Src tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), or a mitogen activated protein kinase (MAPK) kinase inhibitor (PD98059) significantly reduced Ang II-induced ACAT1 protein expression. Macrophage foam cell formation assessed using acetylated low-density lipoprotein (LDL)-induced CE accumulation was significantly enhanced by Ang II, which was completely inhibited by treatment with candesartan. These results suggested that Ang II enhances foam cell formation by upregulating ACAT1 expression predominantly through the actions of AT(1) receptor via the G protein/c-Src/PKC/MAPK pathway in human monocyte-macrophages.
Kanome
Tomoko
T
Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.
Watanabe
Takuya
T
Nishio
Kae
K
Takahashi
Keiko
K
Hongo
Shigeki
S
Miyazaki
Akira
A
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; C091630:L 162313; D009842:Oligopeptides; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; C060894:CGP 42112A; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1; C081643:candesartan