An unbiased chemical biology screen identifies agents that modulate uptake of oxidized LDL by macrophages.
Macrophage-derived foam cells are thought to play a major role in atherosclerotic lesion formation and progression. An automated assay was established to evaluate the uptake of fluorescently labeled oxidized low-density lipoprotein (oxLDL) by a monocyte/macrophage cell line. The assay was used to screen 480 known bioactive compounds. Twenty-two active compounds were identified. Efficacy studies in peritoneal macrophages demonstrated a high rate of concordance with the initial screening results. Inhibitory compounds confirmed important previous findings and identified new drugs of interest including: 3 blockers of nuclear factor kappab activation, 2 protein kinase C inhibitors, a phospholipase C inhibitor, and 2 antipsychotic drugs. In addition, an opioid receptor agonist was found to increase the oxLDL uptake of macrophages. The involvement of nuclear factor kappaB in oxLDL uptake was validated in peritoneal macrophages in vivo. The results support a model in which oxLDL uptake is dependent on the activation of multiple intracellular signaling pathways that culminate in actin-mediated lipoprotein internalization.
Etzion
Yoram
Y
Center for Cardiovascular Research, Washington University School of Medicine, Box 8086, 660 South Euclid Ave, St Louis, MO 63110, USA.
Hackett
Alice
A
Proctor
Brandon M
BM
Ren
Jie
J
Nolan
Bill
B
Ellenberger
Thomas
T
Muslin
Anthony J
AJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001331:Automation; D001681:Biological Assay; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries; D013450:Sulfones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D014150:Antipsychotic Agents; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011957:Receptors, Opioid; D054852:Small Molecule Libraries; D013450:Sulfones; C099252:oxidized low density lipoprotein; D011493:Protein Kinase C; D010738:Type C Phospholipases