Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans

• Published in: PloS one 2010-07, Vol.5 (7), p.e11589
• Main Authors: Stachon, Peter, Missiou, Anna, Walter, Carina, Varo, Nerea, Colberg, Christian, Wolf, Dennis, Buchner, Maike, von Zur Mühlen, Constantin, Zirlik, Katja, Bode, Christoph, Zirlik, Andreas
• Format: Article
• Language: English
• Subjects: Angiography; Animals; Aorta; Aorta, Abdominal - metabolism; Apolipoproteins; Arteriosclerosis; Atherogenesis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; B cells; Biology; Bone marrow; Cardiology; Cardiovascular diseases; Cardiovascular Disorders; Cardiovascular Disorders/Coronary Artery Disease; Cardiovascular Disorders/Vascular Biology; CD40L protein; Cells, Cultured; Cholesterol; Cholesterol - adverse effects; Cholesterol - blood; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Coronary artery disease; Coronary heart disease; Cytokines; Dietary Fats - adverse effects; Female; Fetuses; Flow Cytometry; Glyceraldehyde-3-phosphate dehydrogenase; Heart; Heart diseases; Hematology; Hematopoiesis - genetics; Hematopoiesis - physiology; Hepatocytes; High cholesterol diet; Humans; Immunohistochemistry; Inflammation; Interleukin 1; Ligands; Lipids; Liver; Liver Transplantation; Liver transplants; Low density lipoprotein receptors; Lymphocytes T; Macrophages; Mice; Mice, Mutant Strains; Necrosis; Plaques; Polymerase Chain Reaction; Pregnancy; Receptor density; Receptors, LDL - genetics; Receptors, LDL - physiology; Residential density; Ribonucleic acid; RNA; Rodents; Signaling; Smooth muscle; T cells; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; Weight Gain - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011589

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. 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. 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.