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(Hypertension. 2007;49:1378.)
© 2007 American Heart Association, Inc.

Original Articles

Regulation of Scavenger Receptor Class BI Gene Expression by Angiotensin II in Vascular Endothelial Cells

Xiao Yu; Koji Murao; Hitomi Imachi; Wen-Ming Cao; Junhua Li; Kensuke Matsumoto; Takamasa Nishiuchi; Rania A.M. Ahmed; Norman C.W. Wong; Hiroaki Kosaka; Terry G. Unterman; Toshihiko Ishida

From the Division of Endocrinology and Metabolism, Department of Internal Medicine (X.Y., K.Murao, H.I., W.-M.C., J.L., K.Matsumoto, T.N., R.A.M.A., T.I.), and Department of Cardiovascular Physiology (H.K.), Faculty of Medicine, Kagawa University, Kagawa, Japan; the Departments of Medicine and Biochemistry and Molecular Biology (N.C.W.W.), Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada; and the Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois at Chicago College of Medicine and Jesse Brown VA Medical Center.

Correspondence to Koji Murao, Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail mkoji{at}kms.ac.jp

High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. In this process, a scavenger receptor of the B class (SR-BI)/human homologue of SR-BI, CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from high-density lipoprotein. In endothelial cells, high-density lipoprotein activates endothelial NO synthase via hSR-BI/CLA-1. Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis and modulates the expression of endothelial NO synthase. In the present study, we have examined the role of Ang II on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells. Our results showed that endogenous expression of hSR-BI/CLA-1 was suppressed by exposure to Ang II in human umbilical vein endothelial cells. Administration of the Ang II type-1 receptor blocker olmesartan inhibited Ang II–induced hSR-BI/CLA-1 protein repression. In Ang II–treated cells, high-density lipoprotein had no effect on endothelial NO synthase activation. Ang II decreased transcriptional activity of the hSR-BI/CLA-1 promoter. The inhibitory effect of Ang II on hSR-BI/CLA-1 promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of human umbilical vein endothelial cells to Ang II elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt inhibits the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the hSR-BI/CLA-1 abolished the ability of Ang II to suppress promoter activity. Together, these results indicate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway participates in Ang II suppression of hSR-BI/CLA-1 expression and suggests that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin–angiotensin system.

Key Words: angiotensin II • hSR-BI/CLA-1 • HDL • Akt • FoxO1 • HUVEC