Oxidation of low-density lipoprotein cholesterol following administration of poloxamer 407 to mice results from an indirect effect.J Cardiovasc Pharmacol. 2007 Apr; 49(4):246-52.JC
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.