The Biological Role of Apurinic/Apyrimidinic Endonuclease1/Redox Factor-1 as a Therapeutic Target for Vascular Inflammation and as a Serologic Biomarker

Lee, Yu Ran; Joo, Hee Kyoung; Jeon, Byeong Hwa

doi:10.3390/biomedicines8030057

Cited by 21 publications

(20 citation statements)

References 72 publications

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“…Increasing evidence indicates that APE1/Ref-1 expression is upregulated in several types of cancer, and in cardiovascular and inflammatory disorders [13]. APE1/Ref-1 is highly expressed in hypertensive rats [36] and in human atherosclerotic plaques [37].…”

Section: Discussionmentioning

confidence: 99%

“…It is important to uncover the mechanisms behind APE1/Ref-1 secretion. APE/Ref-1 can be secreted by using non-classical secretion pathways because of the absence of a leading peptide sequence [13]. The secretion of APE1/Ref-1 is mediated by ATP-binding cassette A1 (ABCA1) transporter or vesicular formation [46,47].…”

Section: Discussionmentioning

confidence: 99%

“…While biologically active APE1/Ref-1 can be secreted from cells, the biological function of extracellular APE1/Ref-1 remains unclear. Extracellular APE1/Ref-1 is believed to participate in circulating surveillance for oxidative damage [13]. Additionally, the biological utility of serologic APE1/Ref-1 in cardiovascular disorders has been reported in coronary arterial disorders [14] and murine myocarditis [15], suggesting that APE1/Ref-1 level in blood is correlated with angina or myocardial injury.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…APE1/Ref-1 is a multifunctional protein that can be secreted from cells. In addition to its anti-inflammatory activity and modulation of redox status, APE1/Ref-1 is part of the DNA base repair pathway, affects several types of transcriptional factors, and thereby is essential for genomic stability [ 85 ]. The results showed that the levels of APE/Ref-1 mRNA increased significantly in the hippocampus of rats that were challenged with kainic acid and treated with raloxifene, compared to kainic acid challenged rats that were not treated with kainic acid.…”

Section: Intracellular Mechanisms (Nongenomic and Genomic) Modulatmentioning

confidence: 99%

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

Veenman

2020

IJMS

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Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects—fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson’s disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health—on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer’s disease, raloxifene may not cure diagnosed Alzheimer’s disease. However, the onset of Alzheimer’s disease may be delayed or arrested by raloxifene’s capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer’s disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer’s disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

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“…In this case, APE1's role seems to be interesting to examine. Recently, a study characterized AP endnonuclease as a serological marker for vascular inflammation [122]. Moreover, Jin and co-workers observed that high concentrations of AP endonuclease strongly correlated with myocardial injury.…”

Section: Apurinic/apyrimidinic Endonuclease 1 In Monocyte Cells As a mentioning

confidence: 99%

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

Betlej

Bator

Pyrkosz

et al. 2020

Genes

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Monocytes, which play a crucial role in the immune system, are characterized by an enormous sensitivity to oxidative stress. As they lack four key proteins responsible for DNA damage response (DDR) pathways, they are especially prone to reactive oxygen species (ROS) exposure leading to oxidative DNA lesions and, consequently, ROS-driven apoptosis. Although such a phenomenon is of important biological significance in the regulation of monocyte/macrophage/dendritic cells’ balance, it also a challenge for monocytic mechanisms that have to provide and maintain genetic stability of its own DNA. Interestingly, apurinic/apyrimidinic endonuclease 1 (APE1), which is one of the key proteins in two DDR mechanisms, base excision repair (BER) and non-homologous end joining (NHEJ) pathways, operates in monocytic cells, although both BER and NHEJ are impaired in these cells. Thus, on the one hand, APE1 endonucleolytic activity leads to enhanced levels of both single- and double-strand DNA breaks (SSDs and DSBs, respectively) in monocytic DNA that remain unrepaired because of the impaired BER and NHEJ. On the other hand, there is some experimental evidence suggesting that APE1 is a crucial player in monocytic genome maintenance and stability through different molecular mechanisms, including induction of cytoprotective and antioxidant genes. Here, the dual face of APE1 is discussed.

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The Biological Role of Apurinic/Apyrimidinic Endonuclease1/Redox Factor-1 as a Therapeutic Target for Vascular Inflammation and as a Serologic Biomarker

Cited by 21 publications

References 72 publications

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

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

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

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