HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages.
We previously reported that mevalonate starvation elicited by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced cholesterol accumulation promoted in murine macrophages by acetylated LDL (AcLDL). In the present study we investigated the cellular mechanism of this effect. Our results indicate that the HMG-CoA reductase inhibitors fluvastatin and simvastatin reduce, in a concentration-dependent manner, more than 50% of the 125I-AcLDL degradation by macrophages. This effect was not due to a decrease of lysosomal enzyme activity, and it was paralleled by the retention of AcLDL-associated cholesteryl ester in the incubation medium. The ability of fluvastatin to inhibit AcLDL degradation was completely overcome by mevalonate and its derivative geranylgeraniol. Evaluation at 4 degrees C of 125I-AcLDL binding to plasma membrane suggested that the inhibitory effect of fluvastatin on lipoprotein catabolism was not due to a decreased expression of scavenger receptors. Fluorescent microscope analysis of cellular internalization of AcLDL labeled with the fluorochrome 3,3'-dioctadecyl indocarbocyanine demonstrated that fluvastatin inhibits lipoprotein endocytosis, an effect reversed by mevalonate. Studies performed with native 125I-LDL indicated that fluvastatin did not inhibit but rather increased the degradation of LDL taken up by the normal LDL receptor. These results exclude a generalized depression of the cellular endocytotic activity by the drug. The ability of fluvastatin to reduce AcLDL catabolism and cholesterol esterification was more pronounced in cholesterol-enriched macrophages compared with normal cells. In conclusion, the present results demonstrate that HMG-CoA reductase inhibitors may reduce the in vitro cholesterol accumulation in macrophages by inhibiting AcLDL endocytosis.
Bernini
F
F
Institute of Pharmacology and Pharmacognosy, University of Parma, Italy.
Scurati
N
N
Bonfadini
G
G
Fumagalli
R
R
D000818:Animals; D002232:Carbocyanines; D002788:Cholesterol Esters / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005456:Fluorescent Dyes; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D019821:Simvastatin
D002232:Carbocyanines; D002788:Cholesterol Esters; D004224:Diterpenes; D005229:Fatty Acids, Monounsaturated; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; C024286:3,3'-dioctadecylindocarbocyanine; D000077340:Fluvastatin; D008148:Lovastatin; D019821:Simvastatin; C017338:geranylgeraniol; D008798:Mevalonic Acid