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.
Sata
M
M
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Walsh
K
K
D000595:Amino Acid Sequence; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008969:Molecular Sequence Data
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein