Role of reactive oxygen species and Bax in oxidized low density lipoprotein-induced apoptosis of human monocytes.
This study investigated the proapoptotic effects of oxidized low density lipoprotein (oxLDL), which plays a key role in atherogenesis, on normal fresh human monocytes isolated from peripheral blood (PBMs), on human monocyte-derived macrophages, and on U937 monocytic cell line. OxLDL were generated by hypochlorous acid (HOCl) treatment of native LDL. We demonstrated that HOCl-oxLDL (200 microg/ml) induced apoptosis in PBMs and U937 cells via the mitochondrial pathway, whereas it failed to induce apoptosis in human monocyte-derived macrophages. OxLDL-induced U937 cells apoptosis involved ROS generation, mitochondrial Bax translocation with a disruption of mitochondrial membrane potential, cytosolic liberation of cytochrome c and subsequently activation of caspases-9 and -3. The interference of ROS scavengers N-acetylcysteine and catalase with HOCl-oxLDL-induced apoptosis further supports the importance of mitochondrial ROS production in this process. Bcl-2 overexpression prevented Bax translocation whereas it failed to prevent ROS generation indicating that ROS is an upstream signal for inducing mitochondrial apoptotic damages. Because monocyte apoptosis could limit early atheroma formation, it will be interesting to identify the signaling pathway(s) induced by HOCl-oxLDL leading to ROS generation. In contrast, monocyte-derived macrophages, which resist to HOCl-oxLDL-induced oxidative stress, may promote atherosclerosis.
Ermak
Natalia
N
Laboratory of Biochemistry A, Necker Hospital, Paris, France.
Lacour
Bernard
B
Drüeke
Tilman B
TB
Vicca
Stéphanie
S
D017209:Apoptosis; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D008077:Lipoproteins, LDL; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C099252:oxidized low density lipoprotein; D006997:Hypochlorous Acid; D045304:Cytochromes c