Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE−/− Mice

Abstract

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is involved in DNA base repair and reducing activity. However, the role of APE1/Ref-1 in atherosclerosis is unclear. Herein, we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E (ApoE−/−) mice fed with a Western-type diet. We found that serologic APE1/Ref-1 was strongly correlated with vascular inflammation in these mice. Neutrophil/lymphocyte ratio (NLR), endothelial cell/macrophage activation, and atherosclerotic plaque formation, reflected by atherosclerotic inflammation, were increased in the ApoE−/− mice fed with a Western-type diet. APE1/Ref-1 expression was upregulated in aortic tissues of these mice, and was co-localized with cells positive for cluster of differentiation 31 (CD31) and galectin-3, suggesting endothelial cell/macrophage expression of APE1/Ref-1. Interestingly, APE1/Ref-1 plasma levels of ApoE−/− mice fed with a Western-type diet were significantly increased compared with those of the mice fed with normal diet (15.76 ± 3.19 ng/mL vs. 3.51 ± 0.50 ng/mL, p < 0.05), and were suppressed by atorvastatin administration. Correlation analysis showed high correlation between plasma APE1/Ref-1 levels and NLR, a marker of systemic inflammation. The cut-off value for APE1/Ref-1 for predicting atherosclerotic inflammation at 4.903 ng/mL showed sensitivity of 100% and specificity of 91%. We conclude that APE1/Ref-1 expression is upregulated in aortic endothelial cells/macrophages of atherosclerotic mice, and that plasma APE1/Ref-1 levels could predict atherosclerotic inflammation.

Clinical value of serum Ape1/Ref-1 combined with TGF-β1 monitoring in predicting the occurrence of radiation pneumonitis (RP) in non-small cell lung cancer patients

“…The treatment of RP mice with Cistanche acid can effectively reduce the inflammation and oxidative stress in the lungs, indicating that the occurrence of RP is mainly related to the activation of the TGF-β1/vascular endothelial growth factor signaling pathway (22). Studies have shown that Ape1/Ref-1 is an important regulator of inflammatory indicators, which 4 Analysis of serum apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1), transforming growth factor β1 (TGF-β1), and the combination of both in predicting the occurrence of radiation pneumonitis regulates the level of inflammatory factors in the body through multiple transcription factors, such as activator protein 1 (AP-1), nuclear transcription factor-kappa B (NF-kB), and amino-terminal fragment (ATF) (23). However, the correlation analysis in the present study showed that there is a positive correlation between Ape1/Ref-1 and TGF-β1, indicating that Ape1/Ref-1 may regulate the level of body inflammatory factors, such as TGF-β1, through a certain transcription factor, but its specific mechanism of action still needs further research.…”

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

“…APE1/Ref-1 is also highly expressed in retinal pericytes, choroidal endothelial cells and retinal endothelial cells and is upregulated in tissues where there is inflammation [ 28 , 29 , 30 ]. Furthermore, evidence suggests that secretion of APE1/Ref-1 into the extracellular milieu can act as a serological biomarker for vascular inflammation and other chronic diseases [ 27 , 31 , 32 , 33 ]. Acetylated APE1/Ref-1 has also been shown to be secreted from cells via the ATP binding cassette transporter A1 [ 33 ].…”

“…APE1/Ref-1 is also increased in conditions such as ischemia, hypoxia and inflammation, and APE1/Ref-1 serum levels are elevated in mice with acute viral myocarditis, suggesting that APE1/Ref-1 plays a role in inflammatory conditions such as myocarditis [ 32 ]. Additional studies demonstrated increased APE1/Ref-1 expression in aortic endothelial cell macrophages of atherosclerotic plaques [ 31 ]. Taking this together, APE1/Ref-1 could potentially be used as a biomarker to assess the degree of vascular inflammation.…”

17β-Estradiol Increases APE1/Ref-1 Secretion in Vascular Endothelial Cells and Ovariectomized Mice: Involvement of Calcium-Dependent Exosome Pathway

“…Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein suggested as a new biomarker of vascular inflammation [1,2]. Basically, APE1/Ref-1 plays roles in transcriptional regulation through redox modification and base excision repair [3].…”

“…Basically, APE1/Ref-1 plays roles in transcriptional regulation through redox modification and base excision repair [3]. Since it was first reported in 2013 that APE1/Ref-1 secretion is increased by intracellular hyperacetylation [4], it has subsequently been reported that its secretion is increased in lipopolysaccharide-induced endotoxemic animal models [5], apolipoprotein E-deficient mice fed Western-type diets [1], and patients with coronary artery disease [6], suggesting its usefulness as a new biomarker for vascular inflammation.…”