Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1

Miyuki Kumano-Kuramochi, Yuuki Shimozu, Chika Wakita, Mayumi Ohnishi-Kameyama, Takahiro Shibata, Shigeru Matsunaga, Yuko Takano-Ishikawa, Jun Watanabe, Masao Goto, Qiuhong Xie, Shiro Komba, Koji Uchida, Sachiko Machida

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)171-180
Number of pages10
JournalBiochemical Journal
Issue number1
Publication statusPublished - Feb 15 2012
Externally publishedYes


  • 4-Hydroxy-2-nonenal-histidine adduct (HNE-histidine adduct)
  • 4-Hydroxy-2-nonenal-modified protein (HNE-modified protein)
  • Atherosclerosis
  • Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)
  • Oxidized low-density lipoprotein (OxLDL)
  • Scavenger receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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