Endothelial cell apoptosis induced by oxidized LDL is associated with the down-regulation of the cellular caspase inhibitor FLIP.

Fas (CD-95/APO-1) is a death receptor that initiates an apoptotic signal when activated by its ligand, FasL. Normal vascular endothelial cells are resistant to Fas-mediated apoptosis though they express both Fas and FasL. Oxidized low density lipoprotein (OxLDL) or lysophosphatidylcholine (LPC), a major component of OxLDL, induces endothelial cell suicide by sensitizing endothelial cells to Fas-mediated apoptosis. Here, we show that endothelial cell apoptosis by OxLDL and LPC-C16:0 was dose-dependent and correlated with down-regulation of FLICE-inhibitory protein (FLIP), an intracellular caspase inhibitor. FLIP down-regulation also occurred when endothelial cells were treated with toxic doses of LPC-C18:0 or minimally modified low density lipoprotein (LDL). In contrast, FLIP was not down-regulated by native LDL, acetylated LDL, LPC-C12:0, cholesterol, or 7-ketocholesterol, which are not toxic to endothelial cells. The cytotoxicity of oxidized lipids was reversed by transfecting endothelial cells with a FLIP expression plasmid. The results demonstrate, for the first time, FLIP regulation under conditions that lead to pathological tissue destruction.