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Atherosclerosis. 2017 Dec;267:1-9. doi: 10.1016/j.atherosclerosis.2017.10.016. Epub 2017 Oct 14.

Electronegative L5-LDL induces the production of G-CSF and GM-CSF in human macrophages through LOX-1 involving NF-κB and ERK2 activation.

Author information

1
Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
2
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: pychang@ntu.edu.tw.
3
Department of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: lsc@ntu.edu.tw.

Abstract

BACKGROUND AND AIMS:

Circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are associated with the severity of acute myocardial infarction (AMI). However, what causes increases in G-CSF and GM-CSF is unclear. In this study, we investigated whether L5-low-density lipoprotein (LDL), a mildly oxidized LDL from AMI, can induce G-CSF and GM-CSF production in human macrophages.

METHODS:

L1-LDL and L5-LDL were isolated through anion-exchange chromatography from AMI plasma. Human macrophages derived from THP-1 and peripheral blood mononuclear cells were treated with L1-LDL, L5-LDL, or copper-oxidized LDL (Cu-oxLDL) and G-CSF and GM-CSF protein levels in the medium were determined. In addition, the effects of L5-LDL on G-CSF and GM-CSF production were tested in lectin-type oxidized LDL receptor-1 (LOX-1), CD36, extracellular signal-regulated kinase (ERK) 1, and ERK2 knockdown THP-1 macrophages.

RESULTS:

L5-LDL but not L1-LDL or Cu-oxLDL significantly induced production of G-CSF and GM-CSF in macrophages. In vitro oxidation of L1-LDL and L5-LDL altered their ability to induce G-CSF and GM-CSF, suggesting that the degree of oxidation is critical for the effects. Knockdown and antibody neutralization experiments suggested that the effects were caused by LOX-1. In addition, nuclear factor (NF)-κB and ERK1/2 inhibition resulted in marked reductions of L5-LDL-induced G-CSF and GM-CSF production. Moreover, knockdown of ERK2, but not ERK1, hindered L5-LDL-induced G-CSF and GM-CSF production.

CONCLUSIONS:

The results indicate that L5-LDL, a naturally occurring mild oxidized LDL, induced G-CSF and GM-CSF production in human macrophages through LOX-1, ERK2, and NF-κB dependent pathways.

KEYWORDS:

Electronegative LDL; Granulocyte colony-stimulating factor (G-CSF); Granulocyte macrophage colony-stimulating factor (GM-CSF); Lectin-type oxidized LDL receptor-1 (LOX-1); Macrophage

[Indexed for MEDLINE]

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