Atherosclerosis is an inflammatory response to accumulation of
cholesterol in the artery wall.
Low-density lipoproteins (
LDL) accumulate and are oxidized to proinflammatory compounds in the arterial intima during
hypercholesterolemia, leading to activation of endothelial cells, macrophages, and T cells. We sought to define the role of
oxidized LDL (
oxLDL) in the
poloxamer 407 (P-407)-induced mouse model of dose-dependent
hyperlipidemia and
atherosclerosis developed in our laboratory. The hyperlipidemic agent P-407 was evaluated for its ability to oxidize native
LDL in vitro as determined by measuring the rate of formation of conjugated dienes, as well as
malondialdehyde (MDA) production using the
thiobarbituric acid reactive substances assay. Additionally, plasma obtained from C57BL/6 mice treated with P-407 for 100 days and maintained on either a normal diet or a diet supplemented with 0.5% w/w
cholic acid was assayed for both MDA and
lipid hydroperoxide content. Lastly, plasma from these same groups of mice was analyzed for the presence of
immunoglobulin (Ig) G and
IgM autoantibodies against
oxLDL. Our results indicate that P-407 is unable to directly oxidize native
LDL in vitro. However, plasma obtained from P-407-treated mice demonstrated a significant (P < 0.05) increase in the content of oxidized
lipids, but showed a significant (P < 0.05) decrease in the concentration of
lipid hydroperoxides when compared to controls. Both plasma
IgG and
IgM antibodies to MDA-modified
LDL (MDA-
LDL) were significantly (P < 0.05) elevated in P-407-treated mice, as was
IgG1 anti-MDA-
LDL, whereas the titer of
IgG2a anti-MDA-
LDL was significantly (P < 0.05) reduced. We suggest that P-407 causes oxidation of
LDL in vivo by an indirect mechanism and we further conclude that P-407-induced
hypercholesterolemia in C57BL/6 mice is associated with T cell-dependent (
IgG) and T cell-independent (
IgM) B-cell responses to MDA-
LDL.