Oxidation-dependent effects of oxidized LDL: proliferation or cell death

Abstract

Oxidized low-density lipoprotein (oxLDL) induces a wide range of cellular responses to produce atherosclerotic lesion, but key factors determining the response are not understood. In this study, purified LDL was oxidized with copper sulfate, and its physical properties and the related biological responses were investigated. The average hydrodynamic diameter of the lightly oxidized LDL was approximately 25 nm and its Rf value relative to nLDL on agarose gel was between 1.0 and 1.25. The diameter of the extensively oxidized LDL was over 30 nm, the Rf value was over 2.0. A 24 h-exposure of resting RAW264.7 macrophage cells to 100 µ µ µ µg/ml of the lightly oxidized LDL induced proliferation and macrophage activation whereas the extensively oxidized LDL induced cell death at the same concentration. In contrast, 200 µ µ µ µg/ ml of oxLDL caused cell death regardless of oxidation degree. Short incubation (4-6 h) of the highly oxidized LDL (100 µ µ µ µg/ml) also resulted in cell proliferation. OxLDL-induced cell death showed mixed characteristics of apoptosis and/or necrosis depending on the strength and duration of the insult. These results suggest that cellular responses induced by oxLDL be dependent on the oxidation degree, the duration of exposure, and the concentration of oxLDL.

Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels

“…Several factors may account for this apparent contradiction, but we believe the most important is that the pro-survival effect of ox-LDL is seen at concentrations between 10 and 75 g/ml, whereas at higher concentrations cytotoxicity predominates (19,54). Nearly all reports of ox-LDL-induced apoptosis or cytotoxicity involve ox-LDL concentrations in excess of 100 g/ml.…”

Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage

“…Mouse RAW264.7 cells are a macrophagelike cell line and can be induced to form foam cells in the presence of oxLDL (Supplementary information, Figure S1) [24]. It could also be induced to form foam cells by berberine without the addition of oxLDL (Figure 2A).…”

“…The promotion of atherosclerosis resulted from berberine-induced in vivo foam cell formation. Using RAW264.7 cells, which can be induced by oxidized LDL (oxLDL) to form foam cells [24], we have identified that berberine induces the expression of scavenger receptor A (SR-A) through modulating the PI3-kinase signaling pathway. Specifically, by inactivating PPARγ, berberine inhibits PTEN expression and thus enhances PI3-kinase signaling.…”

Role of macrophage and smooth muscle cell apoptosis in association with oxidized low-density lipoprotein in the atherosclerotic development

“…OxLDL has a transient role in the mitogenic effect of macrophages, but finally causes cell death through the induction of apoptosis and necrosis. 31,32 Several factors such as ischemia, inflammatory cytokines, and the accumulation of toxic substances may also affect cell death in atherosclerotic plaques. 11 In this study, as for the relation of oxLDL to smooth muscle cell apoptosis, the apoptotic smooth muscle cell index increased with atherosclerotic development, and the apoptotic smooth muscle cells were detected mainly in the shoulder region and fibrous cap, where oxLDL-positive cells were predominant.…”