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(Circulation. 2000;101:1372.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques

Potential Implications for Inflammation and Plaque Instability

Bernhard Schieffer, MD; Elisabeth Schieffer, MD; Denise Hilfiker-Kleiner, PhD; Andres Hilfiker, PhD; Petri T. Kovanen, MD; Maija Kaartinen, MD; Jörg Nussberger, MD; Wolfgang Harringer, MD; Helmut Drexler, MD

From the Department of Cardiology (B.S., E.S., D.H.-K., P.T.K., H.D.) and Department of Cardiovascular Surgery (W.H.), Medizinische Hochschule, Hannover, Germany; Wihuri Research Institute (A.H., M.K.), Helsinki, Finland; and the Division D’Hypertension (J.N.), Centre Hospitaliaire Universitaire Vaudois, Suissse.

Correspondence to Helmut Drexler, MD, Department of Cardiology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany. E-mail Drexler.Helmut{at}MH-Hannover.de

Background—Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease.

Methods and Results—Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT₁) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (n=12), in atherectomy samples from patients with unstable angina (culprit lesion; n=8), and in ruptured coronary arteries from patients who died of MI (n=13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT₁ receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells.

Conclusions— Ang II, AT₁ receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT₁ receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes.

Key Words: interleukins • angiotensin • angina • myocardial infarction • arteries • receptors

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				A. Hilfiker, D. Hilfiker-Kleiner, M. Fuchs, K. Kaminski, A. Lichtenberg, H.-J. Rothkotter, B. Schieffer, and H. Drexler Expression of CYR61, an Angiogenic Immediate Early Gene, in Arteriosclerosis and Its Regulation by Angiotensin II Circulation, July 9, 2002; 106(2): 254 - 260. [Abstract] [Full Text] [PDF]

				A.D. Pradhan and P.M. Ridker Do atherosclerosis and type 2 diabetes share a common inflammatory basis? Eur. Heart J., June 1, 2002; 23(11): 831 - 834. [Full Text] [PDF]

				G. Plenz, H. Eschert, M. Erren, T. Wichter, M. Bohm, M. Flesch, H. H. Scheld, and M. C. Deng The interleukin-6/interleukin-6-receptorsystem is activated in donor hearts J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1508 - 1512. [Abstract] [Full Text] [PDF]

				J. A. Ambrose and E. E. Martinez A New Paradigm for Plaque Stabilization Circulation, April 23, 2002; 105(16): 2000 - 2004. [Abstract] [Full Text] [PDF]

				C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]

				D J Brull, J Sanders, A Rumley, G D Lowe, S E Humphries, and H E Montgomery Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release Heart, March 1, 2002; 87(3): 252 - 255. [Abstract] [Full Text] [PDF]

				D. Hilfiker-Kleiner, A. Hilfiker, B. Schieffer, D. Engel, D. L Mann, K. C Wollert, and H. Drexler TNF{alpha} decreases {alpha}MHC expression by a NO mediated pathway: role of E-box transcription factors for cardiomyocyte specific gene regulation Cardiovasc Res, February 1, 2002; 53(2): 460 - 469. [Abstract] [Full Text] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part II: AT1 Receptor Regulation Circulation, January 29, 2002; 105(4): 530 - 536. [Full Text] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]

				M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, V. Esteban, Y. Suzuki, S. Mezzano, J.J. Plaza, and J. Egido Role of the Renin-Angiotensin System in Vascular Diseases: Expanding the Field Hypertension, December 1, 2001; 38(6): 1382 - 1387. [Abstract] [Full Text] [PDF]

				E. Lindmark, E. Diderholm, L. Wallentin, and A. Siegbahn Relationship Between Interleukin 6 and Mortality in Patients With Unstable Coronary Artery Disease: Effects of an Early Invasive or Noninvasive Strategy JAMA, November 7, 2001; 286(17): 2107 - 2113. [Abstract] [Full Text] [PDF]

				D.J. Brull, H.E. Montgomery, J. Sanders, S. Dhamrait, L. Luong, A. Rumley, G.D.O. Lowe, and S.E. Humphries Interleukin-6 Gene -174G>C and -572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1458 - 1463. [Abstract] [Full Text] [PDF]

				S. Keidar, R. Heinrich, M. Kaplan, T. Hayek, and M. Aviram Angiotensin II Administration to Atherosclerotic Mice Increases Macrophage Uptake of Oxidized LDL: A Possible Role for Interleukin-6 Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1464 - 1469. [Abstract] [Full Text] [PDF]

				Z. G. Laszik, X. J. Zhou, G. L. Ferrell, F. G. Silva, and C. T. Esmon Down-Regulation of Endothelial Expression of Endothelial Cell Protein C Receptor and Thrombomodulin in Coronary Atherosclerosis Am. J. Pathol., September 1, 2001; 159(3): 797 - 802. [Abstract] [Full Text] [PDF]

				C. U. Chae, R. T. Lee, N. Rifai, and P. M. Ridker Blood Pressure and Inflammation in Apparently Healthy Men Hypertension, September 1, 2001; 38(3): 399 - 403. [Abstract] [Full Text] [PDF]

				H. Sakamoto, M. Aikawa, C. C. Hill, D. Weiss, W. R. Taylor, P. Libby, and R. T. Lee Biomechanical Strain Induces Class A Scavenger Receptor Expression in Human Monocyte/Macrophages and THP-1 Cells : A Potential Mechanism of Increased Atherosclerosis in Hypertension Circulation, July 3, 2001; 104(1): 109 - 114. [Abstract] [Full Text] [PDF]

				G. G. Neri Serneri, M. Boddi, L. Poggesi, I. Simonetti, M. Coppo, M. L. Papa, G. F. Lisi, M. Maccherini, R. Becherini, A. Boncompagni, et al. Activation of cardiac renin-angiotensin system in unstable angina J. Am. Coll. Cardiol., July 1, 2001; 38(1): 49 - 55. [Abstract] [Full Text] [PDF]

				R. S. Munford Statins and the Acute-Phase Response N. Engl. J. Med., June 28, 2001; 344(26): 2016 - 2018. [Full Text] [PDF]

				S. Blankenberg, H. J. Rupprecht, C. Bickel, C. Espinola-Klein, G. Rippin, G. Hafner, M. Ossendorf, K. Steinhagen, and J. Meyer Cytomegalovirus Infection With Interleukin-6 Response Predicts Cardiac Mortality in Patients With Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2915 - 2921. [Abstract] [Full Text] [PDF]