Haplotype-Based Case-Control Study on Human Apurinic/Apyrimidinic Endonuclease 1/Redox Effector Factor-1 Gene and Essential Hypertension

Naganuma, Takahiro; Nakayama, Tomohiro; Sato, Naoyuki; Fu, Zhen-Yan; Soma, Masayoshi; Yamaguchi, Mai; Shimodaira, Masanori; Aoi, Noriko; Usami, Ron

doi:10.1038/ajh.2009.221

Cited by 16 publications

(13 citation statements)

References 32 publications

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“…8-oxodG is one of the most abundant lesions in oxidatively damaged DNA and was found to induce mutations through G-to-T transversions (7). Oxidatively damaged DNA has been recognized to be associated with the development of some degenerative diseases, essential hypertension (37), and cancer, including kidney tumors (8,21). Nrf2 is able to protect cells from oxidative DNA damage in vivo: Nrf2-deficient, but not wild-type, mice that are exposed to diesel exhaust particles showed increased levels of 8-oxodG in bronchial epithelial cells (1,38), pointing out the importance of Nrf2 in the fight against oxidative DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells BothIn VitroandIn Vivo

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et al. 2014

Antioxidants & Redox Signaling

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Aims: An increased kidney cancer risk was found in hypertensive patients, who frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. The capacity of kidney cells to up-regulate transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2), a key regulator of the cellular antioxidative defense, as a prevention of aldosterone-induced oxidative damage was investigated both in vitro and in vivo. Results: Aldosterone activated Nrf2 and increased the expression of enzymes involved in glutathione (GSH) synthesis and detoxification. This activation depended on the mineralocorticoid receptor (MR) and oxidative stress. In vitro, Nrf2 activation, GSH amounts, and target gene levels decreased after 24 h, while oxidant levels remained high. Nrf2 activation could not protect cells against oxidative DNA damage, as aldosterone-induced double-strand breaks and 7,8-dihydro-8-oxo-guanine (8-oxodG) lesions steadily rose. The Nrf2 activator sulforaphane enhanced the Nrf2 response both in vitro and in vivo, thereby preventing aldosterone-induced DNA damage. In vivo, Nrf2 activation further had beneficial effects on the aldosterone-caused blood pressure increase and loss of kidney function. Innovation: This is the first study showing the activation of Nrf2 by aldosterone. Moreover, the results identify sulforaphane as a substance that is capable of preventing aldosteroneinduced damage both in vivo and in vitro. Conclusion: Aldosterone-induced Nrf2 adaptive response cannot neutralize oxidative actions of chronically increased aldosterone, which, therefore could be causally involved in the increased cancer incidence of hypertensive individuals. Enhancing the cellular antioxidative defense with sulforaphane might exhibit beneficial effects. Antioxid. Redox Signal. 21, 2126-2142.

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Section: Discussionmentioning

confidence: 99%

Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells BothIn VitroandIn Vivo

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et al. 2014

Antioxidants & Redox Signaling

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“…APE1/Ref-1 can modulate susceptibility toward these human diseases via its dysregulation, post-translational modifications or polymorphism in its sequence, as observed by various research groups for several cancer types (for example, ovarian, gastro-esophageal, pancreatico-biliary, lung, prostate, cervical, colorectal, breast, hepatocellular, bladder, head and neck, gastric, and glial cancers). 71, 134 The same is true for diseases such as CVD, 31, 71, 135 AD, 26, 27, 28, 136 Parkinson's disease (PD), 28, 137 Huntington's disease (HD), 138 amyotropic lateral sclerosis (ALS), 139 cerebral ischemia 140 and HIV pathogenesis. 141 These studies underscore the diverse functional association of APE1/Ref-1 with various human diseases, indicating that this is a promising therapeutic research area for the treatment and management of human diseases.…”

Section: Ape1/ref-1 and Human Diseasesmentioning

confidence: 96%

“…31 In an another study, an association between APE1/Ref- 1 gene polymorphism and essential hypertension was observed. 135 A study was carried out using the COS-7 cell line and an APE1/Ref-1 +/− mouse model to study the role of endogenous APE1/Ref-1 in the regulation of endothelium-dependent vascular tone and systemic blood pressure. 71 Damaged endothelium-dependent vascular relaxation due to reduced eNOS activity and basal endothelial NO production was observed in APE1/Ref-1 +/− mice relative to WT mice.…”

Section: Ape1/ref-1 and Human Diseasesmentioning

confidence: 99%

APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

et al. 2014

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Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1α, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a ‘hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

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“…Previous studies reported that the rs1760944 genetic variant is associated with cerebral infarction, hypertension, and lung cancer susceptibility. ( 14–17 ) However, no studies have reported on the possible association between the rs1760944 polymorphism and gastric cancer survival. Thus, the aim of the present study is to determine the association between APE1 rs1760944 polymorphism and prognosis in gastric cancer in a Chinese population.…”

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A genetic variation in APE1 is associated with gastric cancer survival in a Chinese population

et al. 2011

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Altered DNA repair can be associated with aggressive tumor biology and impact on survival of cancer patients. We investigated whether genetic variation of human apurinic/apyrimidinic (AP) endonuclease, a key multifunctional gene involved in the base excision repair pathway, would play a role in gastric cancer survival outcomes. We genotyped APE1 rs1760944 by the TaqMan method in 925 gastric cancer patients. Analyses of association between the polymorphism and survival outcomes were carried out using the Kaplan-Meier method, Cox proportional hazards models, and the log-rank test. Survival analyses for all patients showed that the differences in median survival time between gastric cancer carriers with APE1 rs1760944 TT (55 months) and those with GT/GG (78 months), were statistically significant (P = 0.025, log-rank test). Kaplan-Meier survival estimates revealed that gastric cancer patients carrying the GT/GG genotypes had a higher survival than TT, and this protective effect was also more pro- A lthough the incidence of gastric cancer has clearly decreased during the past few decades, it still remains one of the most common cancers in the world, and the second most frequent cause of cancer-related death following lung cancer.(1) Many patients have advanced disease at the time of diagnosis, resulting in poor prognosis and worse survival.(2,3) Despite recent advances in early diagnosis and treatment, the 5-year survival rate of gastric cancer still ranges from only 5% to 20%. (4,5) Clinical staging is one available clinical measure of tumor aggression and prognosis, but there are still conspicuous differences even within the same tumor stage. Therefore, it would be useful to improve prognostic accuracy by identifying readily accessible molecular markers that predict some of the variation in clinical outcomes. In recent years, studies had focused on the detection of genetic variants that could play roles in the development and progression of gastric cancer. (6) Base excision repair (BER) for DNA damage, a highly conserved mechanism, has been identified as important for many cancers due to its crucial role in the repair of oxidative and alkylation damage. (7,8) AP endonuclease (APE1) is one of the key genes in short-patch BER. Repair of this DNA damage is initiated by the major AP endonuclease, which specifically recognizes and cleaves the phosphodiester bond on the 5¢-side of the resulting abasic AP site by a hydrolytic mechanism.(9) As the major AP endonuclease in human cells, APE1 (also called HAP1, APEX1, and REF-1), accounts for over 95% of total AP endonuclease activity in most cultured human cell lines. (10,11) As well as its DNA repair activity, APE1 also modulates redox function (11) and transcription. (12,13)

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Haplotype-Based Case-Control Study on Human Apurinic/Apyrimidinic Endonuclease 1/Redox Effector Factor-1 Gene and Essential Hypertension

Abstract: Based on the present results, the G-T-T haplotype appears to be a genetic marker of EH, and the APE1/REF-1 gene appears to be a susceptibility gene for EH.

Cited by 16 publications

References 32 publications

Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells BothIn VitroandIn Vivo

Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells BothIn VitroandIn Vivo

APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

A genetic variation in APE1 is associated with gastric cancer survival in a Chinese population

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