title: Suppression of viability and acetyl-LDL metabolism in RAW 264 macrophage-like and smooth muscle cells by bisphosphonates in vitro.
abstract: Etidronate and clodronate are bisphosphonates that inhibit the development of experimental atherosclerosis. Etidronate decreases the intimamedia thickness of carotid artery even in man. Liposome-encapsulated bisphosphonates inhibit the cellular metabolism of atherogenic, modified low-density lipoprotein (acetyl-LDL) by cultured macrophages. In the present study, the effects of new bisphosphonate tiludronate and nitrogen-containing bisphosphonate alendronate on cell viability and cellular uptake and degradation of acetyl-LDL were investigated in vitro with macrophages and arterial smooth muscle cells, which have a significant role in atherogenesis. Tiludronate and alendronate decreased the viability of RAW 264 macrophages at high concentration (1,000 microM; p < 0.05), while liposome-encapsulated drugs suppressed the viability at concentrations of 30-300 microM. At concentrations greater than or equal to 10 microM, tiludronate and alendronate inhibited the uptake and degradation of acetyl-LDL by RAW 264 cells in a concentration-dependent manner (p < 0.001). None of the bisphosphonates affected the viability of smooth muscle cells, and none but alendronate at a high concentration (1,000 microM) inhibited the uptake and degradation of acetyl-LDL by smooth muscle cells. The results show that tiludronate and alendronate inhibit the atherogenic activity of macrophages in vitro, as shown previously with etidronate and clodronate, providing further evidence for the antiatherogenic effects of bisphosphonates.
authors.affiliation: Department of Pharmacological Sciences, University of Tampere, Tampere, Finland.
authors.forename: O M
authors.initials: OM
authors.lastname: Tuominen
authors.forename: M
authors.initials: M
authors.lastname: Hollmén
authors.forename: O
authors.initials: O
authors.lastname: Jaakkola
authors.forename: J
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: R
authors.initials: R
authors.lastname: Ylitalo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004337:Drug Carriers / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D011817:Rabbits
chemical_list: D004164:Diphosphonates; D004337:Drug Carriers; D006131:Growth Inhibitors; D008077:Lipoproteins, LDL; D008081:Liposomes; C032629:acetyl-LDL; C058651:tiludronic acid