Effects of liposome-encapsulated bisphosphonates on acetylated LDL metabolism, lipid accumulation and viability of phagocyting cells.
Bisphosphonates, the drugs used for the treatment of e.g. osteoporosis, inhibit the development of experimental atherosclerosis. When encapsulated in liposomes, they also inactivate macrophages, which have a key role in atherogenesis. We studied the effects of three clinically used bisphosphonates, i.e. clodronate, etidronate and pamidronate, on 1) the viability of mouse peritoneal macrophages and macrophage-like RAW 264 cells, 2) the degradation of 125I-labeled acetylated LDL by RAW 264 cells, and 3) the formation of LDL-derived foam cells in vitro. Liposome-encapsulated clodronate and pamidronate, but not etidronate, decreased the fraction of viable peritoneal macrophages in a concentration-dependent manner, whereas RAW 264 cells were much more resistant to the cytotoxic effects of bisphosphonates. Preincubation with liposomal clodronate and etidronate inhibited in a concentration-dependent manner the degradation of acetylated LDL in RAW 264 cells, but non-cytotoxic concentrations of liposomal pamidronate had only a weak inhibitory effect. The inhibition was more pronounced by liposomal clodronate than by liposomal etidronate. At high concentrations (500 microg protein/ml) of acetylated and aggregated LDL, RAW 264 cells transformed to foam cells. Preincubation with liposomal clodronate and etidronate reduced the cellular accumulation of acetylated LDL-derived lipids, but the drugs had no effect on the lipid accumulation caused by aggregated LDL. The results suggest that liposomal clodronate and etidronate inhibit the activity of phagocyting cells in internalizing and degrading atherogenic modified LDL.
Ylitalo
R
R
Department of Medical Biochemistry, University of Tampere, Finland.
Mönkkönen
J
J
Ylä-Herttuala
S
S
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects
D004164:Diphosphonates; D008077:Lipoproteins, LDL; D008081:Liposomes; C032629:acetyl-LDL