Published Online
on September 19, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on April 18, 2005
Revised on May 18, 2005

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; and 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.

^* To whom correspondence should be addressed. E-mail: miya{at}med.showa-u.ac.jp.

Abstract--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--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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