title: Minimally oxidized LDL inhibits macrophage selective cholesteryl ester uptake and native LDL-induced foam cell formation.
abstract: Scavenger receptor-mediated uptake of oxidized LDL (oxLDL) is thought to be the major mechanism of foam cell generation in atherosclerotic lesions. Recent data has indicated that native LDL is also capable of contributing to foam cell formation via low-affinity receptor-independent LDL particle pinocytosis and selective cholesteryl ester (CE) uptake. In the current investigation, Cu(2+)-induced LDL oxidation was found to inhibit macrophage selective CE uptake. Impairment of selective CE uptake was significant with LDL oxidized for as little as 30 min and correlated with oxidative fragmentation of apoB. In contrast, LDL aggregation, LDL CE oxidation, and the enhancement of scavenger receptor-mediated LDL particle uptake required at least 3 h of oxidation. Selective CE uptake did not require expression of the LDL receptor (LDL-R) and was inhibited similarly by LDL oxidation in LDL-R(-/-) versus WT macrophages. Inhibition of selective uptake was also observed when cells were pretreated or cotreated with minimally oxidized LDL, indicating a direct inhibitory effect of this oxLDL on macrophages. Consistent with the effect on LDL CE uptake, minimal LDL oxidation almost completely prevented LDL-induced foam cell formation. These data demonstrate a novel inhibitory effect of mildly oxidized LDL that may reduce foam cell formation in atherosclerosis.
authors.affiliation: Department of Veterans Affairs Medical Center, Lexington, KY 40502 Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536 Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Meyer
authors.affiliation: Department of Veterans Affairs Medical Center, Lexington, KY 40502 Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536 Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536 Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Ailing
authors.initials: A
authors.lastname: Ji
authors.affiliation: Department of Veterans Affairs Medical Center, Lexington, KY 40502 Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536 Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536 Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Veterans Affairs Medical Center, Lexington, KY 40502 Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536 Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536 Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536.
authors.forename: Deneys R
authors.initials: DR
authors.lastname: van der Westhuyzen
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein
keywords: LDL oxidation; oxidized low density lipoprotein; selective lipid uptake