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    block this user Werner Muller

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    Faculty of Life Science, University of Manchester, Manchester

    Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.

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    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.

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    Description

    Title : Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.
    Author(s) : Maren Luchtefeld, Heribert Schunkert, Monika Stoll, Tina Selle, Rachel Lorier, Karsten Grote, Christian Sagebiel, Kumaravelu Jagavelu, Uwe J F Tietge, Ulrike Assmus, Konrad Streetz, Christian Hengstenberg, Marcus Fischer, Björn Mayer, Karen Maresso, No
    Abstract : 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.
    Keywords : animals, aorta, aorta metabolism, atherosclerosis, atherosclerosis metabolism, coronary vessels, coronary vessels metabolism, cytokine receptor gp130, cytokine receptor gp130 metabolism, cytokine receptor gp130 physiology, genetic predisposition disease,

    Subject : unspecified
    Area : Other
    Language : English
    Year : 2007

    Affiliations Faculty of Life Science, University of Manchester, Manchester
    Journal : The Journal of Experimental Medicine
    Volume : 204
    Issue : 8
    Publisher : The Rockefeller University Press
    Pages : 1935-1944
    Url : http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2118681&tool=pmcentrez&rendertype=abstract
    Doi : 10.1084/jem.20070120

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    Werner's Peer Evaluation activity

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    • Mahendra Kumar Trivedi, Independent researcher, Las Vegas Naveda, Trivedi Global Inc., Trivedi Science Research Laboratory Pvt. Ltd.
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