The Journal of Experimental Medicine
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Published online July 30, 2007
doi:10.1084/jem.20070120
The Journal of Experimental Medicine, Vol. 204, No. 8, 1935-1944
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Luchtefeld et al.
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ARTICLE

 Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Maren Luchtefeld1, Heribert Schunkert2, Monika Stoll3, Tina Selle1, Rachel Lorier4, Karsten Grote1, Christian Sagebiel1, Kumaravelu Jagavelu1, Uwe J.F. Tietge5, Ulrike Assmus6, Konrad Streetz6, Christian Hengstenberg7, Marcus Fischer7, Björn Mayer2, Karen Maresso4, Nour Eddine El Mokhtari8, Stefan Schreiber8, Werner Müller9, Udo Bavendiek1, Christina Grothusen1, Helmut Drexler1, Christian Trautwein6, Ulrich Broeckel4, and Bernhard Schieffer1

1 Abteilung für Kardiologie und Angiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany
2 Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, 23562 Lübeck, Germany
3 Genetische Epidemiologie vaskulärer Erkrankungen, Leibniz-Institute for Arteriosclerosis Research, Univerity of Münster, 48149 Münster, Germany
4 Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226
5 Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
6 Medizinische Klinik III, RWTH Aachen, 52062 Aachen, Germany
7 Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität Regensburg, 93053 Regensburg, Germany
8 Department of Cardiology, Institute for Clinical Molecular Biology and Department of General Medicine, Christian Albrecht University, D-2300 Kiel, Germany
9 Department of Experimental Immunology, Gesellschaft für Biotechnologische Forschung, D-38124 Braunschweig, Germany

CORRESPONDENCE Bernhard Schieffer: Schieffer.Bernhard{at}MH-Hannover.de

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population–based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.

Abbreviations used: APP, acute phase protein; APR, acute phase response; BMI, body mass index; CAD, coronary artery disease; CNTF, ciliary neurotrophic factor; CT, cardiotrophin; HDL, high-density lipoprotein; IL6ST, IL 6 signal transducer; LIF, leukemia inhibitory factor; MAPK, mitogen-activated protein kinase; MASMC, mouse aortic SMC; MI, myocardial infarction; OR, odds ratio; OSM, oncostatin M; SAA, serum amyloid A; SMC, smooth muscle cell; SNP, single-nucleotide polymorphism; STAT, signal transducer and activator of transcription; TC, total cholesterol.

U. Broeckel and B. Schieffer contributed equally to this paper.

W. Müller's present address is Faculty of Life Sciences, University of Manchester, Manchester, UK, M13 9PT.


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