Oxidized LDL Can Induce Macrophage Survival, DNA Synthesis, and Enhanced Proliferative Response to CSF-1 and GM-CSF

Abstract

Abstract-Modification of low density lipoprotein (LDL), eg, by oxidation, has been proposed as being important for the formation of foam cells and therefore for the development of atherosclerotic plaques. There are a number of reports showing that macrophage-derived foam cells can proliferate in both human and animal lesions, particularly in the early phase of the disease and possibly involving macrophage-colony stimulating factor (M-CSF, or CSF-1). We studied the in vitro effects of oxidized LDL (ox-LDL) on murine bone marrow-derived macrophages (BMMs), a cell population with a high proliferative capacity in vitro in response to CSF-1 and a dependence for survival on the presence of this growth factor. We report here that treatment of BMMs with low doses of ox-LDL, but not with native LDL, led to cell survival, DNA synthesis, and an enhanced response to the proliferative actions of CSF-1 and granulocyte macrophage-CSF (GM-CSF); the effects were dependent on the degree of LDL oxidation. For CSF-1, a synergistic effect was noticeable at suboptimal doses. The effect of ox-LDL occurred even in the absence of endogenous CSF-1 or GM-CSF. Our findings suggest that ox-LDL, and possibly other modified forms of LDL, could maintain macrophage (and foam cell) survival and therefore lengthen their tenure in a plaque; the modified LDL could also cause local macrophage proliferation or "prime" them so that they could proliferate better in response to CSF-1 (and GM-CSF) concentrations that may be present in the atheroma.

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

“…Cell Culture-Bone marrow cells were isolated from the femurs of 6 -8-week-old female CD-1 mice as described (18). Cells were plated for 24 h in RPMI 1640 containing 10% FBS and 10% L-cell conditioned medium as the source of M-CSF.…”

“…Ox-LDL has been shown to promote macrophage recruitment and retention in lesions (13), macrophage proliferation (14 -17), and macrophage survival (18). We showed recently (19) that ox-LDL inhibits apoptosis in cultured bone marrow-derived macrophages (BMDM), whereas native LDL or acetyl LDL had no effect.…”

Resistant Hypertriglyceridemia in a Patient With High Plasma Levels of Apolipoprotein CII

“…A dose response for the ox-LDL effect is provided in the online Figure (please see http://atvb.ahajournals.org) and, as we found before with murine macrophages, 14 doses of ox-LDL Յ50 g/mL generally promoted survival; at these survival-inducing doses, the cells spread on the tissue culture surface and remained attached. In contrast, at higher concentrations, viable cell numbers again declined.…”

“…Oxidized LDL (ox-LDL) was prepared as before. 14 TRL indicates triglyceride-rich lipoproteins. Apolipoproteins CII and CIII were measured in total plasma and after ultracentrifugation to remove VLDL and chylomicrons (triglyceride-VLDL after ultracentrifugation was raised to 1000 mg/dL).…”

“…Our findings on the reversal of cell death by ox-LDL are similar to what we have published previously with murine macrophages. 14 Others have found that human macrophages, derived after maturation from 9-day cultures of monocytes, subsequently showed a proliferative response when treated with 10 to 50 g/mL ox-LDL. 5 We found no evidence of increased DNA synthesis (tritiated thymidine incorporation) over the 5-day period in our ox-LDL-treated human monocytes (data not shown).…”