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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1592.)
© 2001 American Heart Association, Inc.

Vascular Biology

Phosphatidylinositol 3-OH Kinase–Akt/Protein Kinase B Pathway Mediates Gas6 Induction of Scavenger Receptor A in Immortalized Human Vascular Smooth Muscle Cell Line

Wen Ming Cao; Koji Murao; Hitomi Imachi; Makoto Sato; Toru Nakano; Tatsuhiko Kodama; Yasuyuki Sasaguri; Norman C.W. Wong; Jiro Takahara; Toshihiko Ishida

From the First Department of Internal Medicine (W.C., K.M., H.I., M.S., J.T., T.I.), Kagawa Medical University, Kagawa, Japan; Shionogi Research Laboratories (T.N.), Shionogi & Co, Ltd, Osaka, Japan; the Research Center for Advanced Science and Technology (T.K.), University of Tokyo, Tokyo, Japan; the Department of Pathology (Y.S.), University of Occupational and Environment Health, Kitakyushu, Japan; and the Departments of Medicine and Biochemistry & Molecular Biology (N.C.W.W.), Faculty of Medicine, Calgary, Alberta, Canada.

Correspondence to Koji Murao, First Department of Internal Medicine, Kagawa Medical University, 1750-1, Miki-Cho, Kita-Gun, Kagawa 761-0793, Japan. E-mail mkoji{at}kms.ac.jp

Abstract—— The growth arrest–specific gene 6 encodes a secreted protein, Gas6, which was originally identified as the ligand of a receptor, Axl, with tyrosine kinase activity. The class A scavenger receptor (SRA) mediates lipid uptake into cells, leading to the formation of foam cells, an important step in atherogenesis. Although Gas6 induces SRA expression, the underlying mechanism is not clear. In this report, we show that the Gas6-induced expression of SRA was mediated by the phosphatidylinositol 3-OH kinase (PI3-kinase)–serine/threonine kinase (Akt/protein kinase B [PKB]) pathway involving Akt phosphorylation. This pathway was activated by exposure to Gas6. Furthermore, the effect of Gas6 was abrogated by wortmannin, a specific inhibitor of PI3-kinase. We also demonstrated that the constitutively active form of Akt enhanced activity of the SRA promoter but that the dominant-negative mutant of Akt completely abolished the expression of SRA after treatment with Gas6. These results show that the PI3-kinase–Akt/PKB pathway participates in Gas6-induced SRA expression and suggests that the activation of Akt/PKB plays an important role in Gas6-induced atherosclerosis and foam cell formation in human vascular smooth muscle cells.

Key Words: scavenger receptors • Gas6 • Akt/protein kinase B • smooth muscle cells • Axl

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