MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine γ-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2124-2137 ◽  
Author(s):  
Long Wang ◽  
Zhi-Ping Tang ◽  
Wei Zhao ◽  
Bing-Hai Cong ◽  
Jian-Qiang Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Critical Role ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Receptor Subtypes ◽  
Down Regulation ◽  
Neonatal Cardiomyocytes

Abstract Hydrogen sulfide, generated in the myocardium predominantly via cystathionine-γ-lyase (CSE), is cardioprotective. Our previous study has shown that estrogens enhance CSE expression in myocardium of female rats. The present study aims to explore the mechanisms by which estrogens regulate CSE expression, in particular to clarify the role of estrogen receptor subtypes and the transcriptional factor responsible for the estrogenic effects. We found that either the CSE inhibitor or the CSE small interfering RNA attenuated the protective effect of 17β-estradiol (E2) against H2O2- and hypoxia/reoxygenation-induced injury in primary cultured neonatal cardiomyocytes. E2 stimulates CSE expression via estrogen receptor (ER)-α both in cultured cardiomyocytes in vitro and in the myocardium of female mice in vivo. A specificity protein-1 (Sp-1) consensus site was identified in the rat CSE promoter and was found to mediate the E2-induced CSE expression. E2 increases ERα and Sp-1 and inhibits microRNA (miR)-22 expression in myocardium of ovariectomized rats. In primary cardiomyocytes, E2 stimulates Sp-1 expression through the ERα-mediated down-regulation of miR-22. It was confirmed that both ERα and Sp-1 were targeted by miR-22. In the myocardium of ovariectomized rats, the level of miR-22 inversely correlated to CSE, ERα, Sp-1, and antioxidant biomarkers and positively correlated to oxidative biomarkers. In summary, this study demonstrates that estrogens stimulate Sp-1 through the ERα-mediated down-regulation of miR-22 in cardiomyocytes, leading to the up-regulation of CSE, which in turn results in an increase of antioxidative defense. Interaction of ERα, miR-22, and Sp-1 may play a critical role in the control of oxidative stress status in the myocardium of female rats.

scholarly journals Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-α by IGF-1 in Hippocampus of Ovariectomized Rats

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3149-3156 ◽  
Author(s):  
Elin M. Grissom ◽  
Jill M. Daniel
Keyword(s):  
Estrogen Receptor ◽  
Steroid Receptor ◽  
Estrogen Receptor Α ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Independent Manner ◽  
Steroid Receptor Coactivator ◽  
Intracerebroventricular Infusion

In the absence of ovarian estrogens, increased levels of estrogen receptor (ER)α in the hippocampus are associated with improvements in cognition. In vitro evidence indicates that under conditions of low estrogen, growth factors, including Insulin-Like Growth Factor 1 (IGF-1), can activate ERα and regulate ERα-mediated transcription through mechanisms that likely involve modification of phosphorylation sites on the receptor. The goal of the current work was to investigate a role for IGF-1 in ligand-independent activation of ERα in the hippocampus of female rats. Ovariectomized rats received a single intracerebroventricular infusion of IGF-1 and hippocampi were collected 1 or 24 hours later. After 1 h, IGF-1 increased hippocampal levels of phosphorylated ERα at serine 118 (S118) as revealed by Western blotting. Coimmunoprecipitation revealed that at 1 hour after infusion, IGF-1 increased association between ERα and steroid receptor coactivator 1, a histone acetyltransferase that increases transcriptional activity of phosphorylated ERα. IGF-1 infusion increased levels of the ERα-regulated proteins ERα, choline acetyltransferase, and brain-derived neurotrophic factor in the hippocampus 24 hours after infusion. Results indicate that IGF-1 activates ERα in ligand-independent manner in the hippocampus via phosphorylation at S118 resulting in increased association of ERα with steroid receptor coactivator 1 and elevation of ER-regulated proteins. To our knowledge, these data are the first in vivo evidence of ligand-independent actions of ERα and provide a mechanism by which ERα can impact memory in the absence of ovarian estrogens.

Abstract 6253: Increased Expression of Thioredoxin Interacting Protein Promotes Oxidative Stress and Contributes to the Pathogenesis Of Diabetic Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kim A Connelly ◽  
Darren J Kelly ◽  
Michael Zhang ◽  
Kerri Thai ◽  
Andrew Advani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
High Glucose ◽  
Diastolic Heart Failure ◽  
Transgenic Rat ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Neonatal Cardiomyocytes

Background: Alterations in the thioredoxin (TRX) antioxidant system have been implicated in the pathogenesis of cardiac injury, particularly in the diabetic setting. While constitutively present, TRX activity is reduced by the presence of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We hypothesized that by increasing TxnIP, diabetes may reduce TRX activity and contribute to oxidative stress. Methods: Cell culture studies were performed using the H9C2 rat cardiomyoblast cell line and neonatal cardiomyocytes isolated from 1 day old Sprague Dawley rat neonates. In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as a measure of oxidative stress. Results: In- vitro, high glucose (25mmol/l) resulted in increased TxnIP mRNA expression in both neonatal cardiomyocytes as well as H92C cells (2.21 ± 0.6 v 1.00 ± 0.19, p<0.05 compared to normoglycaemic conditions) with a 45% reduction in TRX activity (0.11 ± 0.01 v 0.061± 0.003, p<0.01). In-vivo, diabetes led to a 250% rise in TxnIP mRNA expression compared to control (2.54 ± 0.5 v 1.00 ± 0.11, p<0.001) that was accompanied by a three fold rise in urinary 8-OHdG (680 ± 280 v 1395 ± 391 ng/ml, p<0.001). Conclusion: In both the in vitro and in vivo settings, high glucose leads to TxnIP over-expression associated with reduced TRX activity thereby increasing oxidative stress and implicating this system in the pathogenesis of the cardiac dysfunction that characterizes the diabetic state. Pharmacological manipulation of the TRX-TxnIP system may represent a novel target to reduce diabetic complications.

scholarly journals Estrogen modulates the recruitment of myelopoietic cell progenitors in rat through a stromal cell-independent mechanism involving apoptosis

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2683-2692 ◽  
Author(s):  
NK Shevde ◽  
JW Pike
Keyword(s):  
Estrogen Receptor ◽  
Ovarian Function ◽  
Morphological Changes ◽  
Estrogen Treatment ◽  
Ovariectomized Rats ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protective Effects ◽  
Hematopoietic Stem

Loss of ovarian function leads to a significant increase in the number of bone-resorbing osteoclasts. Estrogen replacement is known to manifest bone protective effects in the treatment of postmenopausal osteoporosis. In the present study, we used ovariectomized rats to examine the effects of estrogen loss at the osteoclast progenitor colony forming unit-granulocyte macrophage (CFU-GM) level. A significant increase in CFU-GM number was observed as early as 7 days following ovariectomy, and correlated directly with an increase in the number of osteoclast-like cells generated in marrow cultures. The increase in CFU-GM following ovariectomy was abrogated in animals that received estrogen treatment in vivo. A similar suppressive effect was observed on CFU-GM number when ovariectomized rat marrow was treated with estrogen in vitro. This effect was blocked in the presence of the estrogen antihormone ICI 164,384. Thus, the data suggest the possibility that estrogen exerts a direct effect on osteoclast progenitors, and does so through the estrogen receptor-mediated mechanism. Ovariectomy also led to an increase in the early hematopoietic stem/progenitor cell population (Thy 1.1+ cells) as determined by FLOW cytometry methods. Morphological changes as well as terminal deoxynucleotidyl transferase assays revealed that estrogen treatment negated growth factor-induced proliferation of these early progenitors by promoting apoptosis. The cellular effects of estrogen in vitro together with the immunocytochemical detection of the estrogen receptor in these cells, strongly support the contention that in addition to osteoclast progenitors such as CFU-GM, earlier hematopoietic progenitors are also unique cellular targets for estrogen action.

scholarly journals The Protective Roles of Estrogen Receptor β in Renal Calcium Oxalate Crystal Formation via Reducing the Liver Oxalate Biosynthesis and Renal Oxidative Stress-Mediated Cell Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Wei Zhu ◽  
Zhijian Zhao ◽  
Fu-Ju Chou ◽  
Li Zuo ◽  
Tongzu Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Nadph Oxidase ◽  
Calcium Oxalate ◽  
Cell Lines ◽  
Ros Production ◽  
Crystal Deposition ◽  
Caox Crystal

Females develop kidney stones less frequently than males do. However, it is unclear if this gender difference is related to altered estrogen/estrogen receptor (ER) signaling. Here, we found that ER beta (ERβ) signals could suppress hepatic oxalate biosynthesis via transcriptional upregulation of the glyoxylate aminotransferase (AGT1) expression. Results from multiple in vitro renal cell lines also found that ERβ could function via suppressing the oxalate-induced injury through increasing the reactive oxygen species (ROS) production that led to a decrease of the renal calcium oxalate (CaOx) crystal deposition. Mechanism study results showed that ERβ suppressed oxalate-induced oxidative stress via transcriptional suppression of the NADPH oxidase subunit 2 (NOX2) through direct binding to the estrogen response elements (EREs) on the NOX2 5′ promoter. We further applied two in vivo mouse models with glyoxylate-induced renal CaOx crystal deposition and one rat model with 5% hydroxyl-L-proline-induced renal CaOx crystal deposition. Our data demonstrated that mice lacking ERβ (ERβKO) as well as mice or rats treated with ERβ antagonist PHTPP had increased renal CaOx crystal deposition with increased urinary oxalate excretion and renal ROS production. Importantly, targeting ERβ-regulated NOX2 with the NADPH oxidase inhibitor, apocynin, can suppress the renal CaOx crystal deposition in the in vivo mouse model. Together, results from multiple in vitro cell lines and in vivo mouse/rat models all demonstrate that ERβ may protect against renal CaOx crystal deposition via inhibiting the hepatic oxalate biosynthesis and oxidative stress-induced renal injury.

scholarly journals The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2–HO-1 Axis

2021 ◽  
Vol 22 (19) ◽  
pp. 10247
Author(s):  
Hao-Yu Chuang ◽  
Li-Yun Hsu ◽  
Chih-Ming Pan ◽  
Narpati Wesa Pikatan ◽  
Vijesh Kumar Yadav ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Lines ◽  
Biological Effects ◽  
Critical Role ◽  
Clinical Samples ◽  
Redox Imbalance ◽  
Signaling Axis ◽  
Resistant Cells

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress. Methods: The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified. Results: NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo. Conclusions: These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

scholarly journals Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yuna Tong ◽  
Shan Liu ◽  
Rong Gong ◽  
Lei Zhong ◽  
Xingmei Duan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Injury ◽  
Related Factor ◽  
Ethyl Vanillin

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

GONADOTROPHIN RELEASE IN VITRO, IN THE PRESENCE AND ABSENCE OF LUTEINIZING HORMONE RELEASING HORMONE, BY PITUITARY GLANDS FROM OVARIECTOMIZED AND SHAM-OPERATED IMMATURE FEMALE RATS OF VARIOUS AGES

1981 ◽  
Vol 88 (3) ◽  
pp. 375-379
Author(s):  
J. DULLAART
Keyword(s):  
Female Rats ◽  
Ovariectomized Rats ◽  
Immature Female ◽  
Releasing Hormone ◽  
Incubation Experiments ◽  
Immature Rats ◽  
Pituitary Glands ◽  
Lh Releasing Hormone

Hemipituitary glands of immature female rats, aged 10, 15, 20, 25, 30 and 35 days and either ovariectomized or sham-operated 5 days earlier, were incubated for 2 h in vitro with or without LH releasing hormone. Concentrations of LH and FSH were determined at the end of the incubations in the incubation media and in the hemipituitary glands, and also in the sera collected at the beginning of the incubation experiments. Results showed that in many instances gonadotrophin release was higher after incubation of glands of ovariectomized rats than with glands of control animals. However, these effects of ovariectomy were much smaller than those observed in vivo and were generally absent in rats of less than 20 days of age. It was concluded that ovariectomy may change the secretory characteristics of the gonadotrophic cells of immature rats but that such changes were largely restricted to immature rats older than 20 days.

scholarly journals Estrus-Cycle Regulation of Cortical Inhibition

2018 ◽  
Author(s):  
Ann M. Clemens ◽  
Constanze Lenschow ◽  
Prateep Beed ◽  
Lanxiang Li ◽  
Rosanna Sammons ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Β ◽  
Cortical Inhibition ◽  
Female Rats ◽  
Estrus Cycle ◽  
Whole Cell ◽  
Fast Spiking ◽  
Whole Cell Recordings

SummaryFemale mammals experience cyclical changes in sexual receptivity known as the estrus-cycle. Little is known about how estrus affects the cortex although alterations in sensation, cognition and the cyclic occurrence of epilepsy suggest brain-wide processing changes. We performedin vivojuxtacellular and whole-cell recordings in somatosensory cortex of female rats and found that the estrus-cycle potently altered cortical inhibition. Fast-spiking interneurons strongly varied their activity with the estrus-cycle and estradiol in ovariectomized females, while regular-spiking excitatory neurons did not change.In vivowhole-cell recordings revealed a varying excitation-to-inhibition-ratio with estrus.In situhybridization for estrogen receptor β (Esr2) showed co-localization with parvalbumin-positive interneurons in deep cortical layers, mirroring the laminar distribution of our physiological findings.In vivoandin vitroexperiments confirmed that estrogen acts locally to increase fast-spiking interneuron excitability through an estrogen receptor β mechanism. We conclude that sex hormones powerfully modulate cortical inhibition in the female brain.

scholarly journals The Key Role of Uric Acid in Oxidative Stress, Inflammation, Fibrosis, Apoptosis, and Immunity in the Pathogenesis of Atrial Fibrillation

2021 ◽  
Vol 8 ◽  
Author(s):  
Yawen Deng ◽  
Fei Liu ◽  
Xiaolei Yang ◽  
Yunlong Xia
Keyword(s):  
Oxidative Stress ◽  
Atrial Fibrillation ◽  
Risk Factor ◽  
Clinical Evidence ◽  
Scientific Evidence ◽  
Critical Role ◽  
Adverse Outcomes

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to numerous adverse outcomes including stroke, heart failure, and death. Hyperuricemia is an important risk factor that contributes to atrium injury and AF, but the underlying molecular mechanism remains to be elucidated. In this review, we discussed the scientific evidence for clarifying the role of hyperuricemia in the pathogenesis of AF. Experimental and Clinical evidence endorse hyperuricemia as an independent risk factor for the incidence of AF. Various in vivo and in vitro investigations showed that hyperuricemia might play a critical role in the pathogenesis of AF at different UA concentrations through the activation of oxidative stress, inflammation, fibrosis, apoptosis, and immunity.

scholarly journals 17β-Estradiol, Aging, Inflammation, and the Stress Response in the Female Heart

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1589-1598 ◽  
Author(s):  
James P. Stice ◽  
Le Chen ◽  
Se-Chan Kim ◽  
J. S. Jung ◽  
A. L. Tran ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cardiac Myocytes ◽  
Cytokine Expression ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
17Β Estradiol ◽  
Old Rats ◽  
Hypoxia Reoxygenation

Abstract Heat shock proteins (HSPs) are a cardioprotective class of proteins induced by stress and regulated by the transcription factor, heat shock factor (HSF)-1. 17β-estradiol (E2) indirectly regulates HSP expression through rapid activation of nuclear factor-κB (NF-κB) and HSF-1 and protects against hypoxia. As males experience a loss of protective cellular responses in aging, we hypothesized that aged menopausal (old ovariectomized) rats would have an impaired HSP response, which could be prevented by immediate in vivo E2 replacement. After measuring cardiac function in vivo, cardiac myocytes were isolated from ovariectomized adult and old rats with and without 9 weeks of E2 replacement. Myocytes were treated with E2in vitro and analyzed for activation of NF-κB, HSF-1, and HSP expression. In addition, we measured inflammatory cytokine expression and susceptibility to hypoxia/reoxygenation injury. Cardiac contractility was reduced in old ovariectomized rats and could prevented by immediate E2 replacement in vivo. Subsequent investigations in isolated cardiac myocytes found that in vitro E2 activated NF-κB, HSF-1, and increased HSP 72 expression in adult but not old rats. In response to hypoxia/reoxygenation, myocytes from adult, but not old, rats had increased HSP 72 expression. In addition, expression of the inflammatory cytokines TNF-α and IL-1β, as well as oxidative stress, were increased in myocytes from old ovariectomized rats; only the change in cytokine expression could be attenuated by in vivo E2 replacement. This study demonstrates that while aging in female rats led to a loss of the cardioprotective HSP response, E2 retains its protective cellular properties.

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