DNA hypermethylation: A novel mechanism of CREG gene suppression and atherosclerogenic endothelial dysfunction.


OBJECTIVE:Cellular repressor of E1A-stimulated genes (CREG), a vasculoprotective molecule, is significantly downregulated in atherosclerotic vessels through unclear mechanisms. While epigenetic regulation is involved in atherosclerosis development, it is not known if the CREG gene is epigenetically regulated. The aim of this study was to assess the potential role of CREG methylation in contributing to atherosclerosis. APPROACH AND RESULTS:Overexpression of DNA methyltransferase (DNMT)3B significantly inhibited CREG expression in human umbilical vein endothelial cells (HUVECs) and human coronary aortic endothelial cells (HCAECs).Conversely, inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5-aza-dC) dose-dependently increased CREG expression. A CREG promoter analysis identified +168 to +255 bp as a key regulatory region and the CG site at +201/+202 bp as a key methylation site. The transcription factor GR-α could bind to the +201/+202 bp CG site promoting CREG transcription, a process significantly inhibited by DNMT3B overexpression. Treatment of cells with oxidized low-density lipoprotein (ox-LDL), a critical atherosclerogenic factor, significantly increased DNMT3B expression, increasing CREG promotor methylation, blocking GR-α binding, and inhibiting CREG expression. Consistently, CG sites in the CREG promoter fragment were hyper-methylated in human atherosclerotic arteries, and CREG expression was significantly reduced. A negative correlation between DNMT3B and CREG expression levels was observed in human atherosclerotic arteries. Finally, Ox-LDL-induced endothelium dysfunction was significantly attenuated by both 5-aza-dC and an anti-oxidative molecular N-acetylcysteine (NAC) administration through rescue the expression of CREG and activation of the p-eNOS/NO pathway. CONCLUSIONS:Our study provides the first direct evidence that DNMT3B-mediated CREG gene hypermethylation is a novel mechanism that contributes to endothelial dysfunction and atherosclerosis development. Blocking CREG methylation may represent a novel therapeutic approach to treat ox-LDL-induced atherosclerosis.


Redox Biol


Redox biology


Liu Y,Tian X,Liu S,Liu D,Li Y,Liu M,Zhang X,Yan C,Han Y




Has Abstract


2020-05-01 00:00:00










  • Do free radical NETwork and oxidative stress disparities in African Americans enhance their vulnerability to SARS-CoV-2 infection and COVID-19 severity?

    abstract::This review focuses on the hypothetical mechanisms for enhanced vulnerability of African Americans to SARS-CoV-2 infection, COVID-19 severity, and increased deaths. A disproportionately higher number of African Americans are afflicted with autoimmune and inflammatory diseases (e.g., diabetes, hypertension, obesity), a...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Kalyanaraman B

    更新日期:2020-10-01 00:00:00

  • Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone.

    abstract::Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species ...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Torrente L,Prieto-Farigua N,Falzone A,Elkins CM,Boothman DA,Haura EB,DeNicola GM

    更新日期:2020-02-01 00:00:00

  • Redox mechanisms in age-related lung fibrosis.

    abstract::Redox signaling and oxidative stress are associated with tissue fibrosis and aging. Aging is recognized as a major risk factor for fibrotic diseases involving multiple organ systems, including that of the lung. A number of oxidant generating enzymes are upregulated while antioxidant defenses are deficient with aging a...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Kurundkar A,Thannickal VJ

    更新日期:2016-10-01 00:00:00

  • Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis.

    abstract::Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2-OA) is an el...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Jobbagy S,Vitturi DA,Salvatore SR,Turell L,Pires MF,Kansanen E,Batthyany C,Lancaster JR Jr,Freeman BA,Schopfer FJ

    更新日期:2019-02-01 00:00:00

  • Sestrin2 modulates cardiac inflammatory response through maintaining redox homeostasis during ischemia and reperfusion.

    abstract::Ischemia heart disease is the leading cause of death world-widely and has increased prevalence and exacerbated myocardial infarction with aging. Sestrin2, a stress-inducible protein, declines with aging in the heart and the rescue of Sestrin2 in the aged mouse heart improves the resistance to ischemic insults caused b...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Ren D,Quan N,Fedorova J,Zhang J,He Z,Li J

    更新日期:2020-07-01 00:00:00

  • Impact of glutathione supplementation of parenteral nutrition on hepatic methionine adenosyltransferase activity.

    abstract:BACKGROUND:The oxidation of the methionine adenosyltransferase (MAT) by the combined impact of peroxides contaminating parenteral nutrition (PN) and oxidized redox potential of glutathione is suspected to explain its inhibition observed in animals. A modification of MAT activity is suspected to be at origin of the PN-a...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Elremaly W,Mohamed I,Rouleau T,Lavoie JC

    更新日期:2016-08-01 00:00:00

  • Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer.

    abstract::Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Chen W,Zou P,Zhao Z,Chen X,Fan X,Vinothkumar R,Cui R,Wu F,Zhang Q,Liang G,Ji J

    更新日期:2016-12-01 00:00:00

  • Selenium-binding protein 1 (SELENBP1) is a marker of mature adipocytes.

    abstract::Selenium-binding protein 1 (SELENBP1) has recently been reported to catalyse the oxidation of methanethiol, an organosulfur compound produced by gut microbiota. Two of the reaction products of methanethiol oxidation, hydrogen peroxide and hydrogen sulphide, serve as signalling molecules for cell differentiation. Indee...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Steinbrenner H,Micoogullari M,Hoang NA,Bergheim I,Klotz LO,Sies H

    更新日期:2019-01-01 00:00:00

  • L-dehydroascorbic acid can substitute l-ascorbic acid as dietary vitamin C source in guinea pigs.

    abstract::Vitamin C deficiency globally affects several hundred million people and has been associated with increased morbidity and mortality in numerous studies. In this study, bioavailability of the oxidized form of vitamin C (l-dehydroascorbic acid or DHA)-commonly found in vitamin C containing food products prone to oxidati...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Frikke-Schmidt H,Tveden-Nyborg P,Lykkesfeldt J

    更新日期:2016-04-01 00:00:00

  • Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress.

    abstract::Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for f...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Chakraborty D,Felzen V,Hiebel C,Stürner E,Perumal N,Manicam C,Sehn E,Grus F,Wolfrum U,Behl C

    更新日期:2019-06-01 00:00:00

  • Redox regulation of microRNAs in endometriosis-associated pain.

    abstract::Endometriosis is a chronic, painful condition with unknown etiology. A differential expression of microRNAs in the endometriotic tissues from women with endometriosis with pain compared to those without suggested a plausible role for miRNA or epigenetic mechanisms in the etiology of endometriotic pain. The peritoneal ...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Wright KR,Mitchell B,Santanam N

    更新日期:2017-08-01 00:00:00

  • Advanced glycation end products and protein carbonyl levels in plasma reveal sex-specific differences in Parkinson's and Alzheimer's disease.

    abstract::Neurodegenerative diseases (NDD) such as Alzheimer's (AD) and Parkinson's disease (PD) are distinct clinical entities, however, the aggregation of key neuronal proteins, presumably leading to neuronal demise appears to represent a common mechanism. It has become evident, that advanced glycation end products (AGEs) tri...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Sharma A,Weber D,Raupbach J,Dakal TC,Fließbach K,Ramirez A,Grune T,Wüllner U

    更新日期:2020-07-01 00:00:00

  • Lactate as a fulcrum of metabolism.

    abstract::Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and c...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Brooks GA

    更新日期:2020-08-01 00:00:00

  • Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia.

    abstract::Keloids exhibit metabolic reprogramming including enhanced glycolysis and attenuated oxidative phosphorylation. Hypoxia induces a series of protective responses in mammalian cells. However, the metabolic phenotype of keloid fibroblasts under hypoxic conditions remains to be elucidated. The present study aimed to inves...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Wang Q,Wang P,Qin Z,Yang X,Pan B,Nie F,Bi H

    更新日期:2021-01-01 00:00:00

  • An emerging perspective on sex differences: Intersecting S-nitrosothiol and aldehyde signaling in the heart.

    abstract::Cardiovascular disease is the leading cause of the death for both men and women. Although baseline heart physiology and the response to disease are known to differ by sex, little is known about sex differences in baseline molecular signaling, especially with regard to redox biology. In this review, we describe current...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Casin KM,Kohr MJ

    更新日期:2020-04-01 00:00:00

  • Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system.

    abstract::Highly active anti-retrovirus therapy (HAART) has been used to block the progression and symptoms of human immunodeficiency virus infection. Although it decreases morbidity and mortality, clinical use of HAART has also been linked to various adverse effects such as severe cardiomyopathy resulting from compromised mito...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Nomura R,Sato T,Sato Y,Medin JA,Kushimoto S,Yanagisawa T

    更新日期:2017-10-01 00:00:00

  • Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons.

    abstract::Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compoun...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Redmann M,Benavides GA,Berryhill TF,Wani WY,Ouyang X,Johnson MS,Ravi S,Barnes S,Darley-Usmar VM,Zhang J

    更新日期:2017-04-01 00:00:00

  • Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential.

    abstract::Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabol...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Du K,Ramachandran A,Jaeschke H

    更新日期:2016-12-01 00:00:00

  • Accelerated FASTK mRNA degradation induced by oxidative stress is responsible for the destroyed myocardial mitochondrial gene expression and respiratory function in alcoholic cardiomyopathy.

    abstract::Chronic alcoholism disrupts mitochondrial function and often results in alcoholic cardiomyopathy (ACM). Fas-activated serine/threonine kinase (FASTK) is newly recognized as a key post-transcriptional regulator of mitochondrial gene expression. However, the modulatory role of FASTK in cardiovascular pathophysiology rem...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Zhang F,Wang K,Zhang S,Li J,Fan R,Chen X,Pei J

    更新日期:2021-01-01 00:00:00

  • Mitochondrial stress signaling in longevity: a new role for mitochondrial function in aging.

    abstract::Mitochondria are principal regulators of cellular function and metabolism through production of ATP for energy homeostasis, maintenance of calcium homeostasis, regulation of apoptosis and fatty acid oxidation to provide acetyl CoA for fueling the electron transport chain. In addition, mitochondria play a key role in c...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Hill S,Van Remmen H

    更新日期:2014-07-27 00:00:00

  • Nitric oxide prevents Aft1 activation and metabolic remodeling in frataxin-deficient yeast.

    abstract::Yeast frataxin homolog (Yfh1) is the orthologue of human frataxin, a mitochondrial protein whose deficiency causes Friedreich Ataxia. Yfh1 deficiency activates Aft1, a transcription factor governing iron homeostasis in yeast cells. Although the mechanisms causing this activation are not completely understood, it is as...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Alsina D,Ros J,Tamarit J

    更新日期:2018-04-01 00:00:00

  • Isocitrate dehydrogenase 2 deficiency aggravates prolonged high-fat diet intake-induced hypertension.

    abstract::The development of hypertension is associated with mitochondrial redox balance disruptions. NADP+-dependent isocitrate dehydrogenase 2 (IDH2) plays an important role in the maintenance of mitochondrial redox balance by producing mitochondrial NADPH, which is an essential cofactor in the reduction of glutathione (from ...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Noh MR,Kong MJ,Han SJ,Kim JI,Park KM

    更新日期:2020-07-01 00:00:00

  • Interrelation between ROS and Ca2+ in aging and age-related diseases.

    abstract::Calcium (Ca2+) and reactive oxygen species (ROS) are versatile signaling molecules coordinating physiological and pathophysiological processes. While channels and pumps shuttle Ca2+ ions between extracellular space, cytosol and cellular compartments, short-lived and highly reactive ROS are constantly generated by vari...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Madreiter-Sokolowski CT,Thomas C,Ristow M

    更新日期:2020-09-01 00:00:00

  • Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIbα.

    abstract:BACKGROUND:Platelets are essential for maintaining haemostasis and play a key role in the pathogenesis of cardiovascular disease. Upon ligation of platelet receptors through subendothelial matrix proteins, intracellular reactive oxygen species (ROS) are generated, further amplifying the platelet activation response. Th...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Carrim N,Arthur JF,Hamilton JR,Gardiner EE,Andrews RK,Moran N,Berndt MC,Metharom P

    更新日期:2015-12-01 00:00:00

  • Neuronal vulnerability to fetal hypoxia-reoxygenation injury and motor deficit development relies on regional brain tetrahydrobiopterin levels.

    abstract::Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after birth following ant...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Vasquez-Vivar J,Shi Z,Jeong JW,Luo K,Sharma A,Thirugnanam K,Tan S

    更新日期:2020-01-01 00:00:00

  • Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling.

    abstract::The generation of excessive amounts of reactive oxygen species (ROS) leads to cellular oxidative stress that underlies a variety of forms of hepatocyte injury and death including that from alcohol. Although ROS can induce cell damage through direct effects on cellular macromolecules, the injurious effects of ROS are m...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Schattenberg JM,Czaja MJ

    更新日期:2014-01-01 00:00:00

  • Teaching the fundamentals of electron transfer reactions in mitochondria and the production and detection of reactive oxygen species.

    abstract::Mitochondria fulfill a number of biological functions which inherently depend on ATP and O2(-•)/H2O2 production. Both ATP and O2(-•)/H2O2 are generated by electron transfer reactions. ATP is the product of oxidative phosphorylation whereas O2(-•) is generated by singlet electron reduction of di-oxygen (O2). O2(-•) is ...

    journal_title:Redox biology

    pub_type: 杂志文章,评审


    authors: Mailloux RJ

    更新日期:2015-01-01 00:00:00

  • Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes.

    abstract::Manganese superoxide dismutase, encoded by the Sod2 gene, is a ubiquitously expressed mitochondrial antioxidant enzyme that is essential for mammalian life. Mice born with constitutive genetic knockout of Sod2 do not survive the neonatal stage, which renders the longitudinal study of the biochemical and metabolic effe...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Cyr AR,Brown KE,McCormick ML,Coleman MC,Case AJ,Watts GS,Futscher BW,Spitz DR,Domann FE

    更新日期:2013-02-05 00:00:00

  • Nitrosative stress in human skeletal muscle attenuated by exercise countermeasure after chronic disuse.

    abstract::Activity-induced nitric oxide (NO) imbalance and "nitrosative stress" are proposed mechanisms of disrupted Ca(2+) homeostasis in atrophic skeletal muscle. We thus mapped S-nitrosylated (SNO) functional muscle proteins in healthy male subjects in a long-term bed rest study (BBR2-2 Study) without and with exercise as co...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Salanova M,Schiffl G,Gutsmann M,Felsenberg D,Furlan S,Volpe P,Clarke A,Blottner D

    更新日期:2013-10-28 00:00:00

  • Absorbance and redox based approaches for measuring free heme and free hemoglobin in biological matrices.

    abstract::Cell-free heme (CFH) and hemoglobin (Hb) have emerged as distinct mediators of acute injury characterized by inflammation and microcirculatory dysfunction in hemolytic conditions and critical illness. Several reports have shown changes in Hb and CFH in specific pathophysiological settings. Using PBS, plasma from patie...

    journal_title:Redox biology

    pub_type: 杂志文章


    authors: Oh JY,Hamm J,Xu X,Genschmer K,Zhong M,Lebensburger J,Marques MB,Kerby JD,Pittet JF,Gaggar A,Patel RP

    更新日期:2016-10-01 00:00:00