Published online before print June 18, 2009, doi: 10.1161/CIRCRESAHA.109.195818
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Submitted on February 17, 2009
Revised on June 2, 2009
Accepted on June 4, 2009
An Unbiased Chemical Biology Screen Identifies Agents That Modulate Uptake of Oxidized LDL by Macrophages
Yoram Etzion ;
From the Center for Cardiovascular Research (Y.E., A.H., B.M.P., J.R., A.J.M.), John Milliken Department of Medicine; and Departments of Biochemistry and Molecular Biophysics (B.N., T.E.) and Cell Biology and Physiology (A.J.M.), Washington University School of Medicine, St Louis, Mo.
* To whom correspondence should be addressed. E-mail: amuslin{at}dom.wustl.edu.
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 
b 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 B 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.
Key words: atherosclerosis • foam cells • oxidized LDL • chemical screening