Bcl-2 alters the balance between apoptosis and necrosis, but does not prevent cell death induced by oxidized low density lipoproteins

Oxidized low density lipoproteins (oxLDL) participate in atherosclerosis pl aque formation, rupture, and subsequent thrombosis. Because oxLDL are toxic to cultured cells and Bcl-2 protein prevents apoptosis, the present work a imed to study whether Bcl-2 may counterbalance the toxicity of oxLDL, Two e xperimental model systems were used in which Bcl-2 levels were modulated: 1 ) lymphocytes in which the (high) basal level of Bcl-2 was reduced by antis ense oligonucleotides; 2) HL60 and HL60/B (transduced by Bcl-2) expressing low and high Bcl-2 levels, respectively. In cells expressing relatively hig h Bcl-2 levels (lymphocytes and HL60/B), oxLDL induced mainly primary necro sis, In cells expressing low Bcl-2 levels (antisense-treated lymphocytes, H L60 and ECV-304 endothelial cells), the rate of oxLDL-induced apoptosis was higher than that of primary necrosis. OxLDL evoked a sustained calcium ris e, which is a common trigger to necrosis and apoptosis since both types of cell death were blocked by the calcium chelator EGTA, Conversely, a sustain ed calcium influx elicited by the calcium ionophore A23187 induced necrosis in cells expressing high Bcl-2 levels and apoptosis in cells expressing lo w Bcl-2 levels. This suggests that Bcl-2 acts downstream from the calcium p eak and inhibits only the apoptotic pathway, not the necrosis pathway, thus explaining the apparent shift from oxLDL-induced apoptosis toward necrosis when Bcl-2 is overexpressed.