This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 97/9/e88    most recent 01.RES.0000190400.46267.7ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takata, Y. Articles by Hsueh, W. A. Search for Related Content PubMed PubMed Citation Articles by Takata, Y. Articles by Hsueh, W. A. Related Collections Gene regulation Mechanism of atherosclerosis/growth factors

(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

This article has been cited by other articles:

				K. Kappert, O. Tsuprykov, J. Kaufmann, J. Fritzsche, I. Ott, M. Goebel, I. N. Bahr, P.-L. Hassle, R. Gust, E. Fleck, et al. Chronic Treatment With Losartan Results in Sufficient Serum Levels of the Metabolite EXP3179 for PPAR{gamma} Activation Hypertension, October 1, 2009; 54(4): 738 - 743. [Abstract] [Full Text] [PDF]

				Y. Zuo, P. Yancey, I. Castro, W. Khan, M. Motojima, I. Ichikawa, A. B. Fogo, M. F. Linton, S. Fazio, and V. Kon Renal Dysfunction Potentiates Foam Cell Formation by Repressing ABCA1 Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1277 - 1282. [Abstract] [Full Text] [PDF]

				K.-H. Su, J.-Y. Tsai, Y. R. Kou, A.-N. Chiang, S.-H. Hsiao, Y.-L. Wu, H.-H. Hou, C.-C. Pan, S.-K. Shyue, and T.-S. Lee Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling Cardiovasc Res, June 1, 2009; 82(3): 468 - 475. [Abstract] [Full Text] [PDF]

				S. Van Linthout, F. Spillmann, M. Lorenz, M. Meloni, F. Jacobs, M. Egorova, V. Stangl, B. De Geest, H.-P. Schultheiss, and C. Tschope Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor Hypertension, April 1, 2009; 53(4): 682 - 687. [Abstract] [Full Text] [PDF]

				E. Caglayan, B. Stauber, A. R. Collins, C. J. Lyon, F. Yin, J. Liu, S. Rosenkranz, E. Erdmann, L. E. Peterson, R. S. Ross, et al. Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator-Activated Receptor {gamma} in Cardiac Fibrosis Diabetes, September 1, 2008; 57(9): 2470 - 2479. [Abstract] [Full Text] [PDF]

				Y. Takata, J. Liu, F. Yin, A. R. Collins, C. J. Lyon, C.-H. Lee, A. R. Atkins, M. Downes, G. D. Barish, R. M. Evans, et al. PPAR{delta}-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis PNAS, March 18, 2008; 105(11): 4277 - 4282. [Abstract] [Full Text] [PDF]

				Y. Takata, H. Osawa, M. Kurata, M. Kurokawa, J. Yamauchi, M. Ochi, W. Nishida, T. Okura, J. Higaki, and H. Makino Hyperresistinemia Is Associated With Coexistence of Hypertension and Type 2 Diabetes Hypertension, February 1, 2008; 51(2): 534 - 539. [Abstract] [Full Text] [PDF]