title: Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1.
abstract: LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is an endothelial scavenger receptor that is important for the uptake of OxLDL (oxidized low-density lipoprotein) and contributes to the pathogenesis of atherosclerosis. However, the precise structural motifs of OxLDL that are recognized by LOX-1 are unknown. In the present study, we have identified products of lipid peroxidation of OxLDL that serve as ligands for LOX-1. We used CHO (Chinese-hamster ovary) cells that stably express LOX-1 to evaluate the ability of BSA modified by lipid peroxidation to compete with AcLDL (acetylated low-density lipoprotein). We found that HNE (4-hydroxy-2-nonenal)-modified proteins most potently inhibited the uptake of AcLDL. On the basis of the findings that HNE-modified BSA and oxidation of LDL resulted in the formation of HNE-histidine Michael adducts, we examined whether the HNE-histidine adducts could serve as ligands for LOX-1. The authentic HNE-histidine adduct inhibited the uptake of AcLDL in a dose-dependent manner. Furthermore, we found the interaction of LOX-1 with the HNE-histidine adduct to have a dissociation constant of 1.22×10(-8) M using a surface plasmon resonance assay. Finally, we showed that the HNE-histidine adduct stimulated the formation of reactive oxygen species and activated extracellular-signal-regulated kinase 1/2 and NF-κB (nuclear factor κB) in HAECs (human aortic endothelial cells); these signals initiate endothelial dysfunction and lead to atherosclerosis. The present study provides intriguing insights into the molecular details of LOX-1 recognition of OxLDL.
authors.affiliation: National Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kumano-Kuramochi
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Shimozu
authors.forename: Chika
authors.initials: C
authors.lastname: Wakita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ohnishi-Kameyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takano-Ishikawa
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Masao
authors.initials: M
authors.lastname: Goto
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Xie
authors.forename: Shiro
authors.initials: S
authors.lastname: Komba
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Sachiko
authors.initials: S
authors.lastname: Machida
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology; D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D008024:Ligands; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C032629:acetyl-LDL; D006639:Histidine; C027576:4-hydroxy-2-nonenal