Abstract 5570: TRAF5 Deficiency Accelerates Atherogenesis in Mice: A Role for TRAF5 as Protective Factor in Atherosclerosis?

Abstract

Background: TNF receptor associated factors (TRAFs) function as cytoplasmic adaptor proteins for cytokines of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFalpha, and IL-1beta, established mediators of atherogenesis. We recently reported over-expression of TRAFs in atheromata, TRAF-dependent inflammatory gene expression in atheromata-associated cell types, and limitation of atherogenesis in mice deficient for TRAF1. Here, we test the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: TRAF5–/LDLR– mice consuming a high cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions compared with LDLR– controls. Intimal lesion size increased by up to 328±11% and 174±15% in sections of the aortic arch and aortic root, respectively (n>13 per group, P<0.01 each). Plaques of TRAF5-deficient animals contained up to 149±15% more lipids (P<0.05) and tended to contain more macrophages and less collagen, characteristics associated with vulnerable plaques in humans. Smooth muscle cell content and lymphocyte content remained unchanged. In vitro, TRAF5-deficient endothelial cells expressed higher levels of the adhesion molecule VCAM-1 and the chemokine KC. Furthermore, TRAF5-deficient macrophages took up increased amounts of acethylated LDL (N=3). Finally, patients suffering from stable coronary heart disease and acute coronary syndrome expressed significantly lower amounts of TRAF5 mRNA in blood than healthy controls (0.026±0.0016 vs. 0.023±0.0018 vs. 0.029±0.0017 TRAF5/GAPDH mRNA, N=325, P<0.01) supporting a protective role of TRAF-5 in atherosclerosis. Conclusions: We present the novel finding that TRAF5 deficiency accelerates atherogenesis in mice. These data identify TRAF5 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.