An unbiased chemical biology screen identifies agents that modulate uptake of oxidized LDL by macrophages

Yoram Etzion, Alice Hackett, Brandon M. Proctor, Jie Ren, Bill Nolan, Thomas Ellenberger, Anthony J. Muslin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 κb 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 κB 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.

Original languageEnglish
Pages (from-to)148-157
Number of pages10
JournalCirculation Research
Volume105
Issue number2
DOIs
StatePublished - 17 Jul 2009
Externally publishedYes

Keywords

  • Atherosclerosis
  • Chemical screening
  • Foam cells
  • Oxidized LDL

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