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 journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)171-180
Number of pages10
JournalBiochemical Journal
Volume442
Issue number1
DOIs
Publication statusPublished - Feb 15 2012
Externally publishedYes

Fingerprint

Oxidized LDL Receptors
Histidine
Lectins
Ligands
Lipid Peroxidation
Atherosclerosis
Class E Scavenger Receptors
Lipids
Scavenger Receptors
Mitogen-Activated Protein Kinase 3
Surface Plasmon Resonance
Mitogen-Activated Protein Kinase 1
Endothelial cells
Surface plasmon resonance
Cricetulus
4-hydroxy-2-nonenal
human OLR1 protein
Ovary
Assays
Reactive Oxygen Species

Keywords

  • 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
  • Cell Biology
  • Molecular Biology

Cite this

Kumano-Kuramochi, M., Shimozu, Y., Wakita, C., Ohnishi-Kameyama, M., Shibata, T., Matsunaga, S., ... Machida, S. (2012). Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1. Biochemical Journal, 442(1), 171-180. https://doi.org/10.1042/BJ20111029

Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1. / Kumano-Kuramochi, Miyuki; Shimozu, Yuuki; Wakita, Chika; Ohnishi-Kameyama, Mayumi; Shibata, Takahiro; Matsunaga, Shigeru; Takano-Ishikawa, Yuko; Watanabe, Jun; Goto, Masao; Xie, Qiuhong; Komba, Shiro; Uchida, Koji; Machida, Sachiko.

In: Biochemical Journal, Vol. 442, No. 1, 15.02.2012, p. 171-180.

Research output: Contribution to journalArticle

Kumano-Kuramochi, M, Shimozu, Y, Wakita, C, Ohnishi-Kameyama, M, Shibata, T, Matsunaga, S, Takano-Ishikawa, Y, Watanabe, J, Goto, M, Xie, Q, Komba, S, Uchida, K & Machida, S 2012, 'Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1', Biochemical Journal, vol. 442, no. 1, pp. 171-180. https://doi.org/10.1042/BJ20111029
Kumano-Kuramochi M, Shimozu Y, Wakita C, Ohnishi-Kameyama M, Shibata T, Matsunaga S et al. Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1. Biochemical Journal. 2012 Feb 15;442(1):171-180. https://doi.org/10.1042/BJ20111029
Kumano-Kuramochi, Miyuki ; Shimozu, Yuuki ; Wakita, Chika ; Ohnishi-Kameyama, Mayumi ; Shibata, Takahiro ; Matsunaga, Shigeru ; Takano-Ishikawa, Yuko ; Watanabe, Jun ; Goto, Masao ; Xie, Qiuhong ; Komba, Shiro ; Uchida, Koji ; Machida, Sachiko. / Identification of 4-hydroxy-2-nonenal-histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1. In: Biochemical Journal. 2012 ; Vol. 442, No. 1. pp. 171-180.
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AU - Wakita, Chika

AU - Ohnishi-Kameyama, Mayumi

AU - Shibata, Takahiro

AU - Matsunaga, Shigeru

AU - Takano-Ishikawa, Yuko

AU - Watanabe, Jun

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AB - 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.

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KW - Oxidized low-density lipoprotein (OxLDL)

KW - Scavenger receptor

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