This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Most of the sudden heart attacks and strokes are caused by vulnerable fatty lesions (atherosclerotic plaques) in vessel walls that are undetectable by clinical evaluation. In conditions such as diabetes and aging, LDL, the lipoprotein that carries bad cholesterol, becomes modified by oxidation and other chemical reactions. The body may recognize the oxidized LDL (oxLDL) as foreign and produce autoantibodies against it. These antibodies can bind to oxLDL and form immune complexes (oxLDL-IC), which are cleared by scavenging cells, the macrophages. Macrophages then transform into lipid-loaded cells (foam cells) and start secreting inflammatory products (cytokines). Cytokines released by macrophages and other activated cells act to promote plaque rupture and harmful consequences such as blood clotting. This project focuses on foam cell activation and survival induced by oxLDL-IC. The receptor Fc gamma RI mediates uptake of oxLDL-IC but the possible role of scavenger receptors in the uptake of oxLDL-IC and whether cross linking of two receptors trigger distinct signaling pathways required to elicit an enhanced macrophage response have not been examined. Our data demonstrate that exposure of U937 cells to oxLDL-IC led to increased cell survival, and to translocation and secretion of sphingosine kinase (SK). SK and its product sphingosine-1-phosphate (S1P) are known to be involved in cell proliferation and suppression of apoptosis (cell death). The central hypothesis of this application is that the process by which exposure of macrophages to oxLDL-IC leads to activation and transformation into foam cells involves the engagement of Fc gamma RI and scavenger receptors, triggering sphingolipid signaling mechanisms that suppress apoptosis and result in extended release of cytokines. The following specific aims will be addressed: 1) characterize the involvement of specific macrophage receptors in the process of macrophage response to oxLDL-IC; and 2) characterize the activated downstream sphingolipid signaling response of macrophages to oxLDL-IC.
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