Crucial Role of Extracellular Signal-Regulated Kinase Pathway in Reactive Oxygen Species-Mediated Endothelin-1 Gene Expression Induced by Endothelin-1 in Rat Cardiac Fibroblasts

Cheng, Cheng Ming; Hong, Hong Jye; Liu, Ju Chi; Shih, Neng Lang; Juan, Shu Hui; Loh, Shih‐Hurng; Chan, Paul; Chen, Jin Jer; Cheng, Tzu-Hurng

doi:10.1124/mol.63.5.1002

Cited by 69 publications

(99 citation statements)

References 38 publications

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“…27 Recently, we also found that the activation of AP-1 is redox-sensitive and might play a key role in ET-1 gene induction. 31 Our present results indicate that resveratrol inhibits strain-induced AP-1 transcriptional activity. The inhibitory effect of resveratrol on strain-induced AP-1 transcriptional activation suggested that the attenuation of strain-induced ROS by resveratrol leads to inhibition of AP-1.…”

Section: Discussionsupporting

confidence: 48%

“…Recent studies provide evidence that ROS may act as second messengers in cells exposed to various stimuli. 27,31 Previous studies from our collaborate laboratory and others have shown that cyclic-strain treatment of endothelial cells can induce intracellular ROS generation. 25,26,32 This ROS generation is sustained at an elevated level as long as the mechanical forces are maintained and returns to basal levels with the removal of the forces.…”

Section: Discussionmentioning

confidence: 99%

“…27,31 With the use of the electrophoretic mobility shift assay, AP-1 binding to the consensus AP-1 binding sequence was assayed in HUVECs with strain treatment for 6 hours ( Figure 5A). Pretreating HUVECs with resveratrol or NAC attenuated the strain-stimulated AP-1 binding activity.…”

Section: Resveratrol Inhibits Strain-increased Ap-1 Transcriptional Amentioning

confidence: 99%

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Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol

et al. 2003

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Abstract-Resveratrol is a phytoestrogen naturally found in grapes and is among the major constituents of wine thought to have a cardioprotective effect. Endothelin-1 (ET-1) is a potent vasopressor synthesized by endothelial cells both in culture and in vivo. The aims of this study were to test the hypothesis that resveratrol may alter strain-induced ET-1 gene expression and to identify the putative underlying signaling pathways in endothelial cells. We show that resveratrol indeed potently inhibits strain-induced ET-1 secretion, ET-1 mRNA level, and ET-1 promoter activity. Resveratrol also inhibits strain-increased NADPH oxidase activity, reactive oxygen species formation, and extracellular signal-regulated kinases1/2 (ERK1/2) phosphorylation. Furthermore, pretreating cells with resveratrol or antioxidant N-acetyl-cysteine decreases strain-increased or hydrogen peroxide-increased ET-1 secretion, ET-1 promoter activity, and ET-1 mRNA and ERK1/2 phosphorylation. Using both the electrophoretic mobility shift assay and a reporter gene assay, resveratrol and N-acetyl-cysteine also attenuated the strain-stimulated activator protein-1 binding activity and activator protein-1 reporter activity. In summary, we demonstrate for the first time that resveratrol inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK1/2 pathway through attenuation of reactive oxygen species formation. Thus, this study provides important new insights in the molecular pathways that may contribute to the proposed beneficial effects of resveratrol in the cardiovascular system. any epidemiological studies show a correlation between a low incidence of coronary heart disease and atherosclerosis and a moderate consumption of red wine. 1,2 The vasoprotective effect of red wine, also known as the "French paradox," is currently best exemplified by transresveratrol (trans-3,5,4Ј-hydroxystilbene). 3,4 Resveratrol has many biological activities, including protection from or reduction of the incidence of coronary heart disease. Resveratrol also has been found to protect the heart from ischemiareperfusion injury. 5 Antioxidant properties of resveratrol appear to be partly responsible for this activity. 5-9 Moreover, resveratrol was shown to relax aortic rings in rats through an endothelium-mediated enhancement of the nitric oxide (NO)-cGMP cascade. 10 Subsequent pharmacological studies indicate a direct relaxant effect of resveratrol on vascular smooth muscle that may exert beneficial effects in cardiovascular disease, though the mechanism of these effects is no known. 11 Recently, Orallo et al 12 demonstrated that the characteristic endothelium-dependent vasorelaxant effect of resveratrol in the rat aorta appeared to be caused by the inhibition of vascular NADH/NADPH oxidase and the subsequent decrease in the generation of basal cellular superoxide anions and, therefore, of NO biotransformation. However, little is known about the cellular/molecular mechanisms whereby resveratrol could protect against coronary heart disease. Indee...

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

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Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol

et al. 2003

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“…AngIIinduced fibroblast expression of endothelin-1, which is profibrotic, involves redox activation of AP-1. 138 Nox4 is reported to participate in TGF-β-induced cardiac myofibroblast differentiation through enhanced Smad2/3 signaling, 139 consistent with effects in other tissues. 10 Inflammatory cells may be strongly profibrotic through the modulation of local cytokine signaling.…”

Section: Interstitial Fibrosis and Extracellular Matrix Remodelingsupporting

confidence: 52%

Redox Signaling in Cardiac Physiology and Pathology

Burgoyne

Mongue‐Din

Eaton

et al. 2012

Circulation Research

426

365

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T he concept that oxidative stress-a pathologically high level of oxidant species in cells-may drive cardiovascular disease progression has led to many clinical trials of interventions, such as antioxidant vitamins. These, however, failed to show efficacy in reducing disease risk and progression. Part of the reason may be the focus on oxidative stress as detrimental neglected the wider role of redox balance and reactive oxygen species (ROS) and reactive nitrogen species in cellular (patho)physiology. Redox signaling-defined as the specific, usually reversible, oxidation/reduction modification of cellular signaling pathway components by a reactive species 1 -is increasingly appreciated as centrally important in many physiological and pathological processes. The main ROS involved in redox signaling are the superoxide anion (O 2 − ) and the more stable nonradical hydrogen peroxide (H 2 O 2 ) to which it dismutates, whereas more powerful oxidants such as hydroxyl are so reactive they are unlikely to be specific or reversible. Redox signaling also involves reactive nitrogen species such as NO and peroxynitrite, the latter being formed from the reaction of O 2 − with NO. 2In the heart, redox signaling is involved in physiological processes (eg, excitation-contraction coupling [ECC], cell differentiation), homoeostatic and stress response pathways (eg, adaptation to hypoxia/ischemia), and pathology (eg, adverse cardiac remodeling, fibrosis). This review covers recent advances in understanding the regulation of production of signaling ROS, their mechanisms of action and molecular targets in cardiac cells, and their involvement in cardiac physiopathology. We focus mainly on cardiomyocytes but redox signaling in other cells (eg, fibroblasts, endothelial cells), and functional cross talks among these are also important. Reactive nitrogen species-dependent regulation has been reviewed elsewhere. 2 ROS SourcesROS are generated as a by-product of cellular respiration and metabolism or by specialized enzymes that seem to be centrally involved in redox signaling. The signaling effects of ROS are influenced by their site of production, precise species, local concentration, and cell compartment-specific antioxidant pools. Major ROS sources in the heart and other tissues include the mitochondrial electron transport chain (ETC), other mitochondrial and metabolic enzymes, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Noxs), and uncoupled NO synthases (NOS). Mitochondrial ETCElectron leakage from the ETC causes 1-electron reduction of O 2 to O 2 − (instead of reduction to H 2 O). Although considered to be because of an electron leak, such ROS may nevertheless contribute to homeostatic redox signals. ROS levels increase significantly during mitochondrial dysfunction. They can trigger the mitochondrial permeability transition (MPT) and lead to further ROS release-termed ROS-induced ROS release 3 -which propagates and amplifies ROS production and effects. ROS from non-ETC sources (eg, Noxs) may also stimulate ETC-depende...

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“…27 In several systems, ET-1 has been also shown to mediate its effect via MAPK pathway. [28][29][30] FN gene has both NF-kB and AP-1 binding site on its promoter and may be positively regulated by both transcription factors. [31][32][33][34][35] Data from our present study would suggest that MAPK pathway may upregulate FN via NF-kB and AP-1.…”

Section: Discussionmentioning

confidence: 99%

Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

Xin

Khan

Chen

et al. 2004

Laboratory Investigation

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Increased extracellular matrix protein deposition and basement membrane thickening are important features of diabetic angiopathy. One key matrix protein that has been shown to be instrumental in basement membrane thickening is fibronectin (FN). We have previously demonstrated that glucose-induced increased expression of endothelin-1 (ET-1), may in part, be responsible for increased FN expression via nuclear factor-jB (NF-jB) and activating protein (AP-1) activation. The present study was aimed at elucidating the mechanism of ET-1 with respect to mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation and glucose-induced FN upregulation. Human endothelial cells were exposed to either low (5 mM) or high (25 mM) glucose levels. Cells in low glucose were also treated with ET-1 peptide (5 nM). In addition, we treated cells exposed to high glucose levels with specific MAPK/ERK inhibitor PD098059 (50 lM), dual ETreceptor antagonist, bosentan (10 lM), and PKC blocker, chelerythrine (1 lM). Following incubation period, RNA and total proteins were extracted for RT-PCR for FN and immunoblot analysis of MAPK/ERK activation. Confocal microscopy was performed for analysis of FN protein and nuclear localization of activated Elk. Electrophoretic mobility shift assay was carried out to detect NF-jB and AP-1 activation. Our data demonstrates that high glucose-induced upregulation of FN messenger RNA and protein levels occur via activation of MAPK/ ERK pathway, which was prevented by treatment of cells with bosentan, PD098059 and PKC blocker chelerythrine. Confocal microscopy demonstrated nuclear localization of phospho-Elk protein. Glucoseinduced FN expression was also associated with protein kinase C, NF-jB, and AP-1 activation. These results suggested that glucose-induced, ET-and PKC-dependent, upregulation of FN is, in part, mediated via MAPK/ ERK activation.

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Crucial Role of Extracellular Signal-Regulated Kinase Pathway in Reactive Oxygen Species-Mediated Endothelin-1 Gene Expression Induced by Endothelin-1 in Rat Cardiac Fibroblasts

Cited by 69 publications

References 38 publications

Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol

Inhibition of Cyclic Strain-Induced Endothelin-1 Gene Expression by Resveratrol

Redox Signaling in Cardiac Physiology and Pathology

Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

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