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(Circulation Research. 2005;97:e88.)
© 2005 American Heart Association, Inc.

UltraRapid Communication

Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages

A Novel Atherosclerotic Effect of Angiotensin II

Yasunori Takata, Van Chu, Alan R. Collins, Christopher J. Lyon, Wei Wang, Florian Blaschke, Dennis Bruemmer, Evren Caglayan, William Daley, Jitsuo Higaki, Michael C. Fishbein, Rajendra K. Tangirala, Ronald E. Law, Willa A. Hsueh

From the Division of Endocrinology, Diabetes, and Hypertension (Y.T., V.C., A.R.C., C.J.L., W.W., F.B., D.B., E.C., R.K.T., R.E.L., W.A.H.) and the Department of Pathology (M.C.F.), David Geffen School of Medicine, University of California, Los Angeles; Second Department of Internal Medicine (Y.T., J.H.), Ehime University School of Medicine, Japan; Division of Endocrinology and Molecular Medicine (D.B.), University of Kentucky College of Medicine, Lexington; Novartis Pharmaceuticals Corporation (W.D.), East Hanover, NJ; and Takeda Pharmaceuticals North America (R.E.L.), Lincolnshire, Ill.

Correspondence to Willa A. Hsueh, MD, Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095. E-mail whsueh{at}mednet.ucla.edu

Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.

Key Words: angiotensin II • ATP-binding cassette transporter A1 • macrophage cholesterol accumulation • fos-related antigen 2

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