title: Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells.
abstract: Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced 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: Lkhagvasuren
authors.initials: L
authors.lastname: Damdindorj
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D050197:Atherosclerosis / Q000139:chemically induced / Q000473:pathology; D002109:Caffeic Acids / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017670:Sodium Compounds / Q000633:toxicity*; D015854:Up-Regulation
chemical_list: D018053:Arsenites; D002109:Caffeic Acids; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495138:Olr1 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D017670:Sodium Compounds; C099252:oxidized low density lipoprotein; C017947:sodium arsenite; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D000111:Acetylcysteine
keywords: 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; 2,7-dichlorofluorescin diacetate; 4′,6-diamidine-2′-phenylindole dihydrochloride; ABCA1; AP-1; ATP-binding cassette sub-family A member 1; Arsenic exposure; Atherosclerosis; C-Jun N-terminal kinases; CAPE; DAPI; DCFH-DA; Dil; ECs; Erk1/2; FACS; GAPDH; ICAM-1; JNK; LOX-1; LXR; MAPK; Molecular biology; N-acetylcysteine; NAC; NF-κB; ROS; Reactive oxygen species (ROS); SA; SR-A; VCAM-1; VSMCS; activator protein 1; caffeic acid phenethylester; eNOS; endothelial cells; endothelial nitric oxide synthetase; extracellular signal-regulated protein kinases 1 and 2; fluorescence-activated cell sorting; glyceraldehyde-3-phosphate dehydrogenase; intercellular adhesion molecule 1; lectin-like oxidized low-density lipoprotein receptor; liver X receptor; mitogen-activated protein kinase; nuclear factor of kappa light polypeptide gene enhancer in B cells; oxLDL; oxidized low-density lipoprotein; reactive oxygen species; scavenger receptor A; sodium arsenite; vascular cell adhesion molecule; vascular smooth muscle cells