Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans.
BACKGROUND
Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.


RESULTS
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography.


CONCLUSIONS
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis.
Stachon
Peter
P
Department of Cardiology, University of Freiburg, Freiburg, Germany.
Missiou
Anna
A
Walter
Carina
C
Varo
Nerea
N
Colberg
Christian
C
Wolf
Dennis
D
Buchner
Maike
M
von Zur Mühlen
Constantin
C
Zirlik
Katja
K
Bode
Christoph
C
Zirlik
Andreas
A
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000009:adverse effects / Q000097:blood; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D016031:Liver Transplantation; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
D024042:Collagen Type I; D004041:Dietary Fats; D011973:Receptors, LDL; D048029:TNF Receptor-Associated Factor 6; D002784:Cholesterol