Our current focus involves the sphingolipid signaling mechanisms which mediate the survival of foam cells (lipid-laden macrophages) and their sustained cell activation in response to modified lipoproteins and lipoprotein-immune complexes. Our goal is to uncover targets in the signaling pathway such as receptors and/or sphingolipids that can have therapeutic implications for blocking cytokine release and prevention of vulnerable atherosclerotic plaques.
Modified Lipoproteins and Atherosclerosis
The transformation of macrophages into foam cells is a critical event in the development of atherosclerosis and defining mechanisms mediating foam cell formation and determining the role of foam cells in the pathology of atherosclerosis is an area of great clinical relevance. Macrophages internalize oxidized LDL immune complexes (oxLDL-IC) via the Fc-γ receptor and transform into activated foam cells. Our data demonstrated that exposure of human monocytic cells to oxLDL-IC leads to increased cell survival compared to oxLDL alone. We examined the effect of oxLDL-IC on sphingosine kinase 1 (SK1), an enzyme implicated in mediating pro-survival and inflammatory responses through the generation of the signaling molecule sphingosine-1-phosphate (S1P), and found oxLDL-IC, but not oxLDL alone, induced an immediate translocation and release of SK1 into the conditioned medium.
This finding indicates that S1P may be generated extracellularly in response to modified LDL immune complexes and may therefore promote cell survival and prolong cytokine release by activated macrophages. Our goal is to uncover mechanisms by which oxLDL-IC suppress apoptosis of foam cells, and reveal specific targets in the signaling pathway that can have therapeutic implications for blocking cytokine release and to prevent formation of vulnerable plaques.