Regression of Oxidative Stress by Targeting eNOS and Nrf2/ARE Signaling: A Guided Drug Target for Cardiovascular Diseases

Ramprasath, Tharmarajan; Vasudevan, Varadaraj; Sundaresan, Sivapatham; Puhari, Shanavas Syed Mohamed; Saso, Luciano; Selvam, Govindan Sadasivam

doi:10.2174/1568026615666150220114417

Cited by 34 publications

(18 citation statements)

References 110 publications

(125 reference statements)

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“…ATO has been frequently reported to induce cellular ROS production in many normal and malignant cells 11 , 16 , 17 . NFE2L2, as a transcription factor, plays a crucial role in regulating genes which contain antioxidant response elements (ARE) in their promoters 18 , 19 ; many of these genes encode proteins involved in the removal of intracellular reactive oxygen species (ROS) 18 , 19 . To explore the molecular mechanisms underlying the induction of HO-1 after exposure to ATO, we analyzed the expression levels of NFE2L2 in the total cellular and the nuclear proteins by Western-blot and Immunocytochemical staining assay.…”

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2

Yue¹,

Zhong²,

Mou³

et al. 2015

Int. J. Med. Sci.

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In a previous study, we found that induced expression of Heme Oxygenase-1 (HO-1) is responsible for the resistance of human osteosarcoma MG63 cells to the chemotherapeutic agent arsenic trioxide (ATO). The present study was aimed at investigating the molecular mechanisms underlying the induction of HO-1 that occurs after exposure of MG63 cells to ATO. First, using RT-QPCT and Western-blot, we found that ATO strongly induced the expression of heme oxygenase-1 (HO-1) in these human osteosarcoma cells. Then by analyzing HO-1 mRNA of MG63 cells exposed to ATO in the presence and absence of a transcription inhibitor Actinomycin-D (Act-D), we demonstrated that ATO activates HO-1 expression in MG63 cells by regulating the transcription of the gene. Finally, through the analysis of the NFE2L2 protein levels among the total cellular and nuclear proteins by Western-blot and Immunocytochemical staning, we determined that ATO enhanced the nuclear translocation of nuclear factor erythroid 2-like 2 (NFE2L2), also known as Nrf2. From these results we have concluded that transcription activation of HO-1 resulting from the nuclear translocation of NFE2L2 is the underlying molecular mechanism for its high induction, which, in turn, is responsible for the resistance of human osteosarcoma cells to ATO treatment.

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Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2

Yue¹,

Zhong²,

Mou³

et al. 2015

Int. J. Med. Sci.

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“…Once the bonds are broken, Nrf2 translocates to the cell nucleus and initiates transcription of antioxidant genes including SOD, NQO1, GCLC, HO-1, MRP2 and P-gP ( 22 ). Imbalance between free radicals and anti-oxidant defense is associated with cellular dysfunctions leading to the pathophysiology of various cardiovascular diseases ( 23 ). Therefore, Nrf2 may be considered as a key regulator in maintenance of normal cardiovascular function.…”

Section: Discussionmentioning

confidence: 99%

Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

et al. 2018

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Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3–10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.

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“…Certainly, several drugs have been developed and tested to stimulate the bioavailability of NO through the regulation of the Nrf2/antioxidant response element (Nrf2/ARE). The combined action of NO and Nrf2/ARE signaling could improve vascular function and confer protection against vascular diseases [ 184 ]. On the other hand, several alternatives to increase Nrf2 have been currently explored, including calorie restriction, ozone therapy, hyperbaric oxygen and physical exercise [ 185 ].…”

Section: Perspectivesmentioning

confidence: 99%

DNA Damage: A Main Determinant of Vascular Aging

Bautista-Niño

Portilla‐Fernandez

Vaughan

et al. 2016

IJMS

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Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indicate that under conditions during which DNA damage accumulates in an accelerated rate, functional decline of the vasculature takes place in a similar but more rapid or more exaggerated way than occurs in the absence of such conditions. Also epidemiological studies suggest a relationship between DNA maintenance and age-related cardiovascular disease. Accordingly, mouse models of defective DNA repair are means to study the mechanisms involved in biological aging of the vasculature. We here review the evidence of the role of DNA damage in vascular aging, and present mechanisms by which genomic instability interferes with regulation of the vascular tone. In addition, we present potential remedies against vascular aging induced by genomic instability. Central to this review is the role of diverse types of DNA damage (telomeric, non-telomeric and mitochondrial), of cellular changes (apoptosis, senescence, autophagy), mediators of senescence and cell growth (plasminogen activator inhibitor-1 (PAI-1), cyclin-dependent kinase inhibitors, senescence-associated secretory phenotype (SASP)/senescence-messaging secretome (SMS), insulin and insulin-like growth factor 1 (IGF-1) signaling), the adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-nuclear factor kappa B (NFκB) axis, reactive oxygen species (ROS) vs. endothelial nitric oxide synthase (eNOS)-cyclic guanosine monophosphate (cGMP) signaling, phosphodiesterase (PDE) 1 and 5, transcription factor NF-E2-related factor-2 (Nrf2), and diet restriction.

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Regression of Oxidative Stress by Targeting eNOS and Nrf2/ARE Signaling: A Guided Drug Target for Cardiovascular Diseases

Cited by 34 publications

References 110 publications

Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2

Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2

Nrf2‑dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin‑induced cardiotoxicity

DNA Damage: A Main Determinant of Vascular Aging

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