This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Keidar, S. Articles by Aviram, M. Search for Related Content PubMed PubMed Citation Articles by Keidar, S. Articles by Aviram, M.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1464.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angiotensin II Administration to Atherosclerotic Mice Increases Macrophage Uptake of Oxidized LDL

A Possible Role for Interleukin-6

Shlomo Keidar; Ronit Heinrich; Marielle Kaplan; Tony Hayek; Michael Aviram

From the Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.

Correspondence to Prof Shlomo Keidar, Rambam Medical Center, Haifa, 31096 Israel. E-mail skeidar{at}rambam.health.gov.il

Abstract—— The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10^-7 mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.

Key Words: angiotensin • losartan • oxidized LDL • CD36 • interleukin-6 • macrophages • atherosclerosis

This article has been cited by other articles:

				L. Chen, A. Frister, S. Wang, A. Ludwig, H. Behr, S. Pippig, B. Li, A. Simm, B. Hofmann, C. Pilowski, et al. Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H987 - H996. [Abstract] [Full Text] [PDF]

				D. Divchev, C. Grothusen, M. Luchtefeld, M. Thoenes, F. Onono, R. Koch, H. Drexler, and B. Schieffer Impact of a combined treatment of angiotensin II type 1 receptor blockade and 3-hydroxy-3-methyl-glutaryl-CoA-reductase inhibition on secretory phospholipase A2-type IIA and low density lipoprotein oxidation in patients with coronary artery disease Eur. Heart J., August 2, 2008; 29(16): 1956 - 1965. [Abstract] [Full Text] [PDF]

				J. Nussberger, J.-F. Aubert, K. Bouzourene, M. Pellegrin, D. Hayoz, and L. Mazzolai Renin Inhibition by Aliskiren Prevents Atherosclerosis Progression: Comparison With Irbesartan, Atenolol, and Amlodipine Hypertension, May 1, 2008; 51(5): 1306 - 1311. [Abstract] [Full Text] [PDF]

				F. Huang, J. C. Thompson, P. G. Wilson, H. H. Aung, J. C. Rutledge, and L. R. Tannock Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development J. Lipid Res., March 1, 2008; 49(3): 521 - 530. [Abstract] [Full Text] [PDF]

				S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]

				Q. Li, Y. Laumonnier, T. Syrovets, and T. Simmet Plasmin Triggers Cytokine Induction in Human Monocyte-Derived Macrophages Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1383 - 1389. [Abstract] [Full Text] [PDF]

				Y. Wen, J. Gu, S. K. Chakrabarti, K. Aylor, J. Marshall, Y. Takahashi, T. Yoshimoto, and J. L. Nadler The Role of 12/15-Lipoxygenase in the Expression of Interleukin-6 and Tumor Necrosis Factor-{alpha} in Macrophages Endocrinology, March 1, 2007; 148(3): 1313 - 1322. [Abstract] [Full Text] [PDF]

				N. Takeda, I. Manabe, T. Shindo, H. Iwata, S. Iimuro, H. Kagechika, K. Shudo, and R. Nagai Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6 Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1177 - 1183. [Abstract] [Full Text] [PDF]

				Y. Takata, V. Chu, A. R. Collins, C. J. Lyon, W. Wang, F. Blaschke, D. Bruemmer, E. Caglayan, W. Daley, J. Higaki, et al. Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages: A Novel Atherosclerotic Effect of Angiotensin II Circ. Res., October 28, 2005; 97(9): e88 - e96. [Abstract] [Full Text] [PDF]

				R. M.P. Arruda, V. A. Peotta, S. S. Meyrelles, and E. C. Vasquez Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension Hypertension, October 1, 2005; 46(4): 932 - 936. [Abstract] [Full Text] [PDF]

				C. Cipolletta, K. E. Ryan, E. V. Hanna, and E. R. Trimble Activation of Peripheral Blood CD14+ Monocytes Occurs in Diabetes Diabetes, September 1, 2005; 54(9): 2779 - 2786. [Abstract] [Full Text] [PDF]

				A. C. Calkin, J. M. Forbes, C. M. Smith, M. Lassila, M. E. Cooper, K. A. Jandeleit-Dahm, and T. J. Allen Rosiglitazone Attenuates Atherosclerosis in a Model of Insulin Insufficiency Independent of Its Metabolic Effects Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1903 - 1909. [Abstract] [Full Text] [PDF]

				M. P. Kim, M. Zhou, and L. M. Wahl Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture J. Leukoc. Biol., July 1, 2005; 78(1): 195 - 201. [Abstract] [Full Text] [PDF]

				A. Nobuhiko, E. Suganuma, V. R. Babaev, A. Fogo, L. L. Swift, M. F. Linton, S. Fazio, I. Ichikawa, and V. Kon Angiotensin II Amplifies Macrophage-Driven Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2143 - 2148. [Abstract] [Full Text] [PDF]

				L. Mazzolai, M. A. Duchosal, M. Korber, K. Bouzourene, J. F. Aubert, H. Hao, V. Vallet, H. R. Brunner, J. Nussberger, G. Gabbiani, et al. Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE-/- Mice Hypertension, September 1, 2004; 44(3): 277 - 282. [Abstract] [Full Text] [PDF]

				T. Hayek, E. Pavlotzky, S. Hamoud, R. Coleman, S. Keidar, M. Aviram, and M. Kaplan Tissue Angiotensin-Converting-Enzyme (ACE) Deficiency Leads to a Reduction in Oxidative Stress and in Atherosclerosis: Studies in ACE-Knockout Mice Type 2 Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2090 - 2096. [Abstract] [Full Text] [PDF]

				R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]

				A. R. Brasier, A. Recinos III, and M. S. Eledrisi Vascular Inflammation and the Renin-Angiotensin System Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266. [Abstract] [Full Text] [PDF]