Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med 2007 Aug 06;204(8):1935-44
Date
08/01/2007Pubmed ID
17664290Pubmed Central ID
PMC2118681DOI
10.1084/jem.20070120Scopus ID
2-s2.0-34547764285 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
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.
Author List
Luchtefeld M, Schunkert H, Stoll M, Selle T, Lorier R, Grote K, Sagebiel C, Jagavelu K, Tietge UJ, Assmus U, Streetz K, Hengstenberg C, Fischer M, Mayer B, Maresso K, El Mokhtari NE, Schreiber S, Müller W, Bavendiek U, Grothusen C, Drexler H, Trautwein C, Broeckel U, Schieffer BAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAorta
Atherosclerosis
Coronary Vessels
Cytokine Receptor gp130
Genetic Predisposition to Disease
Hepatocytes
Humans
Inflammation
Macrophages
Mice
Mice, Inbred C57BL
Polymorphism, Genetic
Risk