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Probucol does not alter acetylated low density lipoprotein uptake by murine peritoneal macrophages
G Ku1, K Schroeder, L F Schmidt
1Merrell Dow Research Institute, Cincinnati, OH 45215.
Abstract:
It has been suggested that the anti-atherogenic effect of probucol (MDL 11,309) in familial hypercholesterolemic rabbits may be due in part to the inhibition of the uptake of modified low density lipoproteins by macrophages in the arterial wall. To test this hypothesis, mice were treated with dietary probucol (0.25%) for fourteen days, peritoneal macrophages were isolated and the uptake of acetylated low density lipoprotein (ALDL) was studied. In addition, peritoneal macrophages from control animals were treated with probucol (200 micrograms/ml) for 24 h in vitro prior to the ALDL uptake assay. The assay involved a fluorescent ALDL probe (dioctadecyltetramethylindocarbocyanine perchlorate-labeled ALDL), and measurement of uptake with a flow cytometer. No differences in ALDL uptake were detected between the control macrophages and macrophages treated with probucol in vitro or macrophages taken from probucol-treated mice.
Insights
Probucol does not inhibit macrophage uptake of acetylated low-density lipoprotein (ALDL) in mice, contrary to suggestions about its anti-atherogenic effects. This study found no impact of probucol on ALDL uptake by macrophages, whether administered in vivo or in vitro.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Probucol's anti-atherogenic effects are potentially linked to inhibiting modified low-density lipoprotein (LDL) uptake by macrophages.
- Familial hypercholesterolemia involves lipid accumulation and arterial wall damage.
Purpose of the Study:
- To investigate whether probucol inhibits the uptake of acetylated low-density lipoprotein (ALDL) by macrophages.
- To test the hypothesis that probucol's anti-atherogenic properties stem from reduced ALDL uptake.
Main Methods:
- Mice were fed a diet containing 0.25% probucol for 14 days.
- Peritoneal macrophages were isolated from mice and from control animals.
- Macrophages were incubated with fluorescently labeled ALDL, and uptake was measured via flow cytometry.
- In vitro experiments involved treating control macrophages with probucol before ALDL exposure.
Main Results:
- No significant difference in ALDL uptake was observed between control macrophages and those treated with probucol, either in vivo or in vitro.
- Dietary probucol administration in mice did not alter macrophage ALDL uptake.
- In vitro probucol treatment of macrophages did not affect their capacity to internalize ALDL.
Conclusions:
- Probucol does not appear to inhibit the uptake of acetylated low-density lipoprotein by macrophages.
- The proposed mechanism for probucol's anti-atherogenic effect via reduced ALDL uptake in macrophages is not supported by this study.
- Further research is needed to elucidate the precise mechanisms underlying probucol's effects on atherosclerosis.