Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.
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.
Abteilung für Kardiologie und Angiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Maren
M
Luchtefeld
Heribert
H
Schunkert
Monika
M
Stoll
Tina
T
Selle
Rachel
R
Lorier
Karsten
K
Grote
Christian
C
Sagebiel
Kumaravelu
K
Jagavelu
Uwe J F
UJ
Tietge
Ulrike
U
Assmus
Konrad
K
Streetz
Christian
C
Hengstenberg
Marcus
M
Fischer
Björn
B
Mayer
Karen
K
Maresso
Nour Eddine
NE
El Mokhtari
Stefan
S
Schreiber
Werner
W
Müller
Udo
U
Bavendiek
Christina
C
Grothusen
Helmut
H
Drexler
Christian
C
Trautwein
Ulrich
U
Broeckel
Bernhard
B
Schieffer
D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D003331:Coronary Vessels / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic; D012306:Risk
C494200:Il6st protein, mouse; D050822:Cytokine Receptor gp130