Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages.
Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. We examined the effects of U-II on ACAT-1 expression and CE accumulation in human monocyte-derived macrophages. U-II increased ACAT activity in a concentration-dependent manner after 7 days in monocyte primary culture. Immunoblotting analysis showed that U-II at 25 nmol/L increased ACAT-1 protein expression level by 2.5-fold, which was completely abolished by anti-U-II antibody, selective UT receptor antagonists (urantide and 4-aminoquinoline), a G-protein inactivator (GDP-beta-S), a c-Src protein tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), a mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059), or a Rho kinase (ROCK) inhibitor (Y27632). Northern blotting analysis indicated that among the 4 ACAT-1 mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the 2.8- and 3.6-kb transcript levels were selectively upregulated by approximately 1.7-fold by U-II (25 nmol/L). Further, U-II (25 nmol/L) significantly increased acetylated LDL (acetyl-LDL)-induced CE accumulation in monocyte-derived macrophages but not scavenger receptor class A (SR-A) function as assessed by endocytic uptake of [(125)I]acetyl-LDL. Our results suggest that U-II may play a novel role in the formation of macrophage-derived foam cells by upregulating ACAT-1 expression via the UT receptor/G-protein/c-Src/PKC/MEK and ROCK pathways but not by SR-A, thus contributing to the relatively rapid development of atherosclerosis in hypertension.
Watanabe
Takuya
T
Department of Biochemistry, Showa University School of Medicine, Tokyo 142-8555, Japan.
Suguro
Toshiaki
T
Kanome
Tomoko
T
Sakamoto
Yu-Ichiro
Y
Kodate
Syuusuke
S
Hagiwara
Tamio
T
Hongo
Shigeki
S
Hirano
Tsutomu
T
Adachi
Mitsuru
M
Miyazaki
Akira
A
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005487:Foam Cells / Q000166:cytology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014579:Urotensins / Q000008:administration & dosage / Q000494:pharmacology*
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D014579:Urotensins; C032629:acetyl-LDL; C029677:urotensin II; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1