Abstract 8635: Novel Role of the Osteoclast-Associated Receptor (oscar) In Oxidative Stress-Mediated Atherogenesis

Abstract

Cross talk between the vascular and the immune system plays a crucial role in cardiovascular diseases including atherosclerosis and ectopic calcification. The osteoclast-associated receptor (OSCAR) is a regulator of osteoclast differentiation and dendritic cell maturation, and recently was implicated as a modulator of osteoimmunology. But the role of OSCAR in vascular biology and its impact on atherogenic processes provoked by pro-inflammatory stimuli is unknown. We recently identified OSCAR on the surface of human primary endothelial cells. Endothelial cell survival was significantly enhanced by activation of OSCAR (+22 %, p<0.001). In contrast, apoptosis was inhibited, as measured by DNA fragmentation (−19 %, p<0.01) and by determination of caspase 3/7 activity (−22 %, p<0.05). Furthermore, OSCAR overexpression increased adhesion of monocytic cells to the endothelium up to 2-fold (p<0.05). In an in-depth proteomic study using stable isotope labelling with amino acids in cell culture (SILAC) more than 2,500 proteins (FDR < 1%) were reproducibly quantified by nano-HPLC/nano-ESI-MS in OSCAR expressing endothelial cells. 116 proteins were determined to be significantly regulated due to OSCAR overexpression, which are mainly involved in cell proliferation, anti-apoptosis, and stress response. Stimulation of endothelial cells with oxidized low-density lipoprotein (oxLDL) caused a time-dependent and dose-dependent induction of OSCAR that was LOX-1-dependent and Ca 2+ -dependent. Specific inhibition of the nuclear factor of activated T cells (NFAT) pathway prevented the oxLDL-mediated increase of endothelial OSCAR expression, and oxLDL induced binding of NFATc1 to the OSCAR promoter as assessed by EMSA and OSCAR promoter analysis. Interestingly, in vivo modified LDL from patients with diabetes mellitus stimulated OSCAR mRNA expression in human endothelial cells 2.5-fold (p<0.01). Furthermore, ApoE knockout mice fed a high-fat diet showed enhanced aortic OSCAR expression (+220%, p<0.01), accompanied by increased NFATc1 expression. Our data suggest that OSCAR, originally described as immunological mediator and regulator of osteoclast differentiation, may also participate in cell activation and inflammation in atherosclerosis.