Necrosis and apoptosis induced by oxidized low density lipoproteins occur through two calcium-dependent pathways in lymphoblastoid cells.
Oxidized low density lipoproteins (LDL) elicit in cultured lymphoblastoid cell lines a delayed and sustained calcium rise followed by a progressive of DNA fragmentation, endogenous proteolysis, and morphological features of necrosis and apoptosis. All these events were blocked by chelating the calcium of the culture medium by EGTA, thus suggesting that the two types of cell death induced by oxidized LDL (necrosis and apoptosis) were subsequent to the rise in calcium. The protease inhibitors leupeptin and antipain were able to block (at least in part) the endogenous proteolysis and the necrotic process, but exhibited no effect on apoptosis and DNA fragmentation. At the opposite, aurintricarboxylic acid and spermine (inhibitors of DNA degradation by endonucleases) inhibit DNA fragmentation and morphological apoptosis, but not endogenous proteolysis and necrosis. These data suggest that cell death induced by oxidized LDL occurs through two calcium-dependent processes triggering 1) on one hand, proteolysis and subsequently necrosis characterized by the loss of cell membrane integrity; and 2) on the other hand, internucleosomal DNA cleavage and subsequently morphological apoptosis. The RNA or protein synthesis inhibitors, actinomycin D and cycloheximide, were completely ineffective in preventing endogenous proteolysis, DNA fragmentation, necrosis, and apoptosis induced by oxidized LDL. The subclassification of the type of apoptosis elicited by oxidized LDL is discussed.
Escargueil-Blanc
I
I
Department of Biochemistry, Faculty of Medicine in Rangueil, University Paul Sabatier, Toulouse, France.
Salvayre
R
R
Nègre-Salvayre
A
A
D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002461:Cell Line, Transformed; D004247:DNA / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000378:metabolism / Q000503:physiopathology*; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000494:pharmacology
D008077:Lipoproteins, LDL; D011480:Protease Inhibitors; D004247:DNA; D002118:Calcium