title: Lipopolysaccharide augments the uptake of oxidized LDL by up-regulating lectin-like oxidized LDL receptor-1 in macrophages.
abstract: There is a growing body of evidence supporting an intimate association of immune activation with the pathogenesis of cardiovascular diseases, including atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) through scavenging receptors promotes the formation of mature lipid-laden macrophages, which subsequently leads to exacerbation of regional inflammation and atherosclerotic plaque formation. In this study, we first examined changes in the mRNA level of the lectin-like oxLDL receptor-1 (LOX-1) in the mouse macrophage cell line RAW264.7 and the human PMA-induced macrophage cell line THP-1 after LPS stimulation. LPS significantly up-regulated LOX-1 mRNA in RAW264.7 cells; LOX-1 cell-surface protein expression was also increased. Flow cytometry and fluorescence microscopy analyses showed that cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with LPS stimulation. The augmented uptake of Dil-oxLDL was almost completely abrogated by treatment with an anti-LOX-1 antibody. Of note, knockdown of Erk1/2 resulted in a significant reduction of LPS-induced LOX-1 up-regulation. Treatment with U0126, a specific inhibitor of MEK, significantly suppressed LPS-induced expression of LOX-1 at both the mRNA and protein levels. Furthermore, LOX-1 promoter activity was significantly augmented by LPS stimulation; this augmentation was prevented by U0126 treatment. Similar results were also observed in human PMA-induced THP-1 macrophages. Taken together, our results indicate that LPS up-regulates LOX-1, at least in part through activation of the Erk1/2 signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of TLR4-mediated aberrant LOX-1 signaling in the pathogenesis of atherosclerosis.
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Ekhtear
authors.initials: E
authors.lastname: Hossain
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Shahnewaj B
authors.initials: SB
authors.lastname: Mannan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein