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(Hypertension. 2005;46:738.)
© 2005 American Heart Association, Inc.

Original Articles

Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

Takuya Watanabe; Toshiaki Suguro; Tomoko Kanome; Yu-ichiro Sakamoto; Syuusuke Kodate; Tamio Hagiwara; Shigeki Hongo; Tsutomu Hirano; Mitsuru Adachi; Akira Miyazaki

From the Department of Biochemistry (T.W., T.K., T. Hagiwara., S.H., A.M.) and First Department of Internal Medicine (T.S., S.K., T. Hirano., M.A.), Showa University School of Medicine, Tokyo, Japan; and Department of Medical Biochemistry, Kumamoto University Graduate School of Medicine and Pharmaceutical Sciences (Y.S.), Japan.

Correspondence to Akira Miyazaki, MD, PhD, Professor and Chairman, Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail miya{at}med.showa-u.ac.jp

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-ß-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 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 [¹²⁵I]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.

Key Words: cholesterol • metabolism • human • macrophages • atherosclerosis • vasoconstriction

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