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.
Luchtefeld
Maren
M
Abteilung für Kardiologie und Angiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Schunkert
Heribert
H
Stoll
Monika
M
Selle
Tina
T
Lorier
Rachel
R
Grote
Karsten
K
Sagebiel
Christian
C
Jagavelu
Kumaravelu
K
Tietge
Uwe J F
UJ
Assmus
Ulrike
U
Streetz
Konrad
K
Hengstenberg
Christian
C
Fischer
Marcus
M
Mayer
Björn
B
Maresso
Karen
K
El Mokhtari
Nour Eddine
NE
Schreiber
Stefan
S
Müller
Werner
W
Bavendiek
Udo
U
Grothusen
Christina
C
Drexler
Helmut
H
Trautwein
Christian
C
Broeckel
Ulrich
U
Schieffer
Bernhard
B
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