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(Circulation. 2004;110:3493-3500.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis

Bernhard Schieffer, MD^*; Tina Selle, PhD^*; Andres Hilfiker, PhD; Denise Hilfiker-Kleiner, PhD; Karsten Grote, PhD; Uwe J.F. Tietge, MD; Christian Trautwein, MD; Maren Luchtefeld, PhD; Christian Schmittkamp, MS; Sylvia Heeneman, PhD; Mat J.A.P. Daemen, MD; Helmut Drexler, MD

From the Departments of Cardiology and Angiology (B.S., T.S., A.H., A.H.-K., K.G., M.L., C.S., H.D.) and of Gastroenterology and Endocrinology (C.T.), Medical School Hannover, Hannover, Germany; Department of Medicine and NWF2 (U.J.F.T.), Charite Campus Mitte, Berlin, Germany; and the Department of Pathology (S.H., M.J.A.P.D.), Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands.

Correspondence to Bernhard Schieffer, MD, Medizinische Hochschule Hannover (MHH), Abteilung Kardiologie und Angiologie, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. E-mail schieffer.bernhard{at}mh-hannover.de

Received July 5, 2004; revision received July 5, 2004; accepted August 25, 2004.

Background— Vascular lipid accumulation and inflammation are hallmarks of atherosclerosis and perpetuate atherosclerotic plaque development. Mediators of inflammation, ie, interleukin (IL)-6, are elevated in patients with acute coronary syndromes and may contribute to the exacerbation of atherosclerosis.

Methods and Results— To assess the role of IL-6 in atherosclerosis, ApoE^–/––IL-6^–/– double-knockout mice were generated, fed a normal chow diet, and housed for 53±4 weeks. Mortality and blood pressure were unaltered. However, serum cholesterol levels and subsequent atherosclerotic lesion formation (oil red O stain) were significantly increased in ApoE^–/––IL-6^–/– mice compared with ApoE^–/–, wild-type (WT), and IL-6^–/– mice. Plaques of ApoE^–/––IL-6^–/– mice showed significantly reduced transcript and protein levels of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, collagen I and V, and lysyl oxidase (by reverse transcriptase-polymerase chain reaction and immunohistochemistry). Recruitment of macrophages and leukocytes (Mac3- and CD45-positive staining) into the atherosclerotic lesion was significantly reduced in ApoE^–/––IL-6^–/– mice. The transcript and serum protein (ELISA) levels of IL-10 were significantly reduced.

Conclusions— Thus, a lifetime IL-6 deficiency enhances atherosclerotic plaque formation in ApoEK^–/––IL-6^–/– mice and leads to maladaptive vascular developmental processes. These observations are consistent with the notion that baseline levels of IL-6 are required to modulate lipid homeostasis, vascular remodeling, and plaque inflammation in atherosclerosis.

Key Words: interleukins • cholesterol • atherosclerosis • inflammation • metalloproteinases

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