Apoptotic pathways involved in U937 cells exposed to LDL oxidized by hypochlorous acid.

Oxidized low-density lipoproteins (oxLDL) play a critical role in atherogenesis. One oxidative pathway of LDL involves myeloperoxidase, which catalyzes the production of hypochlorous acid (HOCl) in monocytes. We investigated the apoptotic mechanism induced by oxLDL, generated by HOCl treatment of native LDL, in human monocytic U937 cell line. The involvement of the mitochondrial apoptotic pathway was analyzed in Bcl-2-overexpressing clones, generated from U937 cells. HOCl-oxLDL induced in U937 cells (i) a marked caspase-dependent increase of apoptosis, (ii) a loss of mitochondrial membrane potential, (iii) a specific activation of caspase-2, -3, -8, and -9, and (iv) a similar degree of apoptosis in presence or absence of anti-Fas and anti-TNF-R1 antibodies. Moreover, the degree of HOCl-oxLDL-induced caspase-3 and -8 activation, and apoptosis was significantly reduced in U937/Bcl-2 cells, with no activation of caspase-9. By contrast, Cu-oxLDL-mediated apoptosis in U937 cells involved exclusively the mitochondrial pathway. In conclusion, the mechanism of HOCl-oxLDL-induced apoptosis in monocytic U937 cells involves the two pathways of apical caspase activation: (i) death receptor-mediated caspase-8 and (ii) mitochondria-mediated caspase-9. This converges in the activation of executing caspases, including caspase-3, and apoptosis. The interference of Bcl-2 overexpression with HOCl-oxLDL-induced apoptosis suggests the importance of mitochondrial involvement in this apoptotic mechanism.

New insights into the effects of the protein moiety of oxidized LDL (oxLDL).

Oxidative stress has been implicated in the cardiovascular complications in chronic renal failure patients. Lipoprotein oxidation is involved in the genesis of atherosclerosis. Both the lipid and the protein moieties of low-density lipoproteins (LDL) are subject to oxidation. We have shown that oxidation of LDL by hypochlorous acid (HOCl) in vitro, reflecting increased myeloperoxidase (MPO) activity in vivo, leads mainly to modifications of apolipoproteins, such that the latter in turn induce high rates of apoptosis in a human monocytic cell line via a caspase-dependent pathway. These in vitro oxidative changes of LDL protein moiety, if shown to occur to a significant extent in uremic patients in vivo, may represent an important pathway in the pathogenesis of atherogenesis.