Stimulation of nitric oxide synthase during oxidative endothelial cell injury

Shimizu, Shunichi; Nomoto, Masaki; Naito, Shinji; Yamamoto, Toshinori; Momose, Kazutaka

doi:10.1016/s0006-2952(97)00399-7

Cited by 34 publications

(18 citation statements)

References 33 publications

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“…Studies in endothelial cells as well as one in vivo study in rat gastric mucosal cells are consistent with our published findings of rapid iNOS changes (54,56). In the study using isolated rat gastric mucosal cells (56), low basal levels of iNOS were noted in control (untreated) mucosa, whereas, after challenge with endotoxin, significant and rapid increases in iNOS activity were detected in the mucosal cells within 1 h, followed by peak levels at 2-4 h (almost identical to the rapid start and peak times for iNOS changes in our Caco-2 cells).…”

Section: Discussionsupporting

confidence: 91%

“…In the study using isolated rat gastric mucosal cells (56), low basal levels of iNOS were noted in control (untreated) mucosa, whereas, after challenge with endotoxin, significant and rapid increases in iNOS activity were detected in the mucosal cells within 1 h, followed by peak levels at 2-4 h (almost identical to the rapid start and peak times for iNOS changes in our Caco-2 cells). Similarly, other studies showed detectable levels of iNOS activity as early as 60 min after H 2 O 2 (0.1-1 mM) challenge (54). In yet another study in endothelial cells, a slight basal expression of iNOS protein (and iNOS mRNA as detected by RT-PCR) was shown in unstimulated cells (63).…”

Section: Discussionmentioning

confidence: 58%

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Key role of PLC-γ in EGF protection of epithelial barrier against iNOS upregulation and F-actin nitration and disassembly

Banan

Zhang

Shaikh

et al. 2003

American Journal of Physiology-Cell Physiology

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Upregulation of inducible nitric oxide synthase (iNOS) is key to oxidant-induced disruption of intestinal (Caco-2) monolayer barrier, and EGF protects against this disruption by stabilizing the cytoskeleton. PLC-␥ appears to be essential for monolayer integrity. We thus hypothesized that PLC-␥ activation is essential in EGF protection against iNOS upregulation and the consequent cytoskeletal oxidation and disarray and monolayer disruption. Intestinal cells were transfected to stably overexpress PLC-␥ or to inhibit its activation and were then pretreated with EGF Ϯ oxidant (H 2O2). Wild-type (WT) intestinal cells were treated similarly. Relative to WT monolayers exposed to oxidant, pretreatment with EGF protected monolayers by: increasing native PLC-␥ activity; decreasing six iNOS-related variables (iNOS activity/protein, NO levels, oxidative stress, actin oxidation/nitration); increasing stable F-actin; maintaining actin stability; and enhancing barrier integrity. Relative to WT cells exposed to oxidant, transfected monolayers overexpressing PLC-␥ (ϩ2.3-fold) were protected, as indicated by decreases in all measures of iNOS-driven pathway and enhanced actin and barrier integrity. Overexpression-induced inhibition of iNOS was potentiated by low doses of EGF. Stable inhibition of PLC-␥ prevented all measures of EGF protection against iNOS upregulation. We conclude that 1) EGF protects against oxidative stress disruption of intestinal barrier by stabilizing F-Actin, largely through the activation of PLC-␥ and downregulation of iNOS pathway; 2) activation of PLC-␥ is by itself essential for cellular protection against oxidative stress of iNOS; and 3) the ability to suppress iNOS-driven reactions and cytoskeletal oxidation and disassembly is a novel mechanism not previously attributed to the PLC family of isoforms. actin cytoskeleton; gut barrier; growth factors; oxidative stress; nitration and carbonylation; reactive nitrogen metabolites; phospholipase C isoform; inflammatory bowel disease; Caco-2 cells THE EPITHELIUM of gastrointestinal (GI) mucosa is a highly selective permeability barrier that normally excludes the passage of harmful proinflammatory molecules (e.g., bacterial endotoxin, immunoreactive antigens) but allows the absorption from the lumen of nutrients and water into the mucosa and the systemic circulation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 58%

Key role of PLC-γ in EGF protection of epithelial barrier against iNOS upregulation and F-actin nitration and disassembly

Banan

Zhang

Shaikh

et al. 2003

American Journal of Physiology-Cell Physiology

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“…It has been reported that H 2 O 2 can increase eNOS promoter activity, eNOS mRNA stability, as well as eNOS activity as measured by the conversion of L-arginine to L-citrulline in bovine aortic endothelial cells (BAECs) (11,41). Previously, our group (47) has shown that eNOS expression increased at lower H 2 O 2 concentration and that BAECs have twofold higher catalase activity than FPAECs.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity

Kumar

Sun

Wedgwood³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Previously, we have reported that endothelial nitric oxide synthase (eNOS) promoter activity is decreased in pulmonary arterial endothelial cells (PAECs) in response to hydrogen peroxide (H(2)O(2)). Thus the objective of this study was to identify the cis-element(s) and transcription factor(s) responsible for oxidant-mediated downregulation of the eNOS gene. Initial promoter experiments in PAECs treated with H(2)O(2) revealed a significant decrease in activity of a promoter fragment containing 840 bp of upstream sequence of the human eNOS gene fused to a luciferase reporter. However, a promoter construct containing only 640 bp of upstream sequence had a significantly attenuated response to H(2)O(2) challenge. As the 840-bp promoter construct had a putative binding site for the transcription factor activator protein-1 (AP-1) that was lacking in the 640-bp construct, we evaluated the effect of H(2)O(2) on promoter activity after mutation of the AP-1 binding sequence (TGAGTCA at -661 to TGAGTtg in the 840-bp construct). Similar to the results seen with the 640 bp, the AP-1 mutant promoter had a significantly attenuated response to H(2)O(2). EMSA revealed decreased binding of AP-1 during H(2)O(2) treatment. Supershift analysis indicated that the AP-1 complex consisted of a c-Jun and FosB heterodimer. Furthermore, in vitro EMSA analysis indicated the c-Jun binding was significantly decreased after H(2)O(2) exposure. Using chromatin immunoprecipitation analysis, we demonstrated decreased binding of AP-1 to the eNOS promoter in vivo in response to H(2)O(2). These data suggest a role of decreased AP-1 binding likely through c-Jun in the H(2)O(2)-mediated decrease in eNOS promoter activity.

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“…It is known that increases in intracellular Ca 2 * ([Ca 3+ ]i) are involved in oxidative stress-induced lethal endothelial cell injury (41,42). We found that hydrogen peroxide markedly increases NOS activity by increasing [Ca 2+ ]¡ several hours after addition in bovine aortic endothelial cells (43). The increases in NOS activity are observed before lethal cell injury.…”

Section: Dysfunction Of Nos By Oxidative Stress and Endothelial Cell mentioning

confidence: 73%

Protective Effect of Tetrahydrobiopterin Against Reactive Oxygen Species- and Nitric Oxide-induced Vascular Endothelial Cell Injury

Shimizu

2002

Pteridines

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Vascular endothelial cells are one of the major biological targets of reactive oxygen species (ROS) in ischemiareperfusion, diabetes, hypercholesterolemia and inflammation. Accumulated evidence has shown that tetrahydrobiopterin (BTI4), which is an essential cefaclor for nitric oxide synthase (NOS) activity, protected the cells against ROS and nitric oxide (NO) toxicities. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal conditions, NOS also produces superoxide anion and hydrogen peroxide when BH4 is decreased, suggesting the possibility that NOS is a source of ROS under pathological conditions. Since 15114 is easily oxidized by ROS, oxidative stress may induce ROS release from NOS by the decomposition of BH4. ÖH4 also has an antioxidative activity and scavenging activity for ROS. In this review, the role of BH4 in the function of' NOS, and the mechanisms underlying the protective effect of BFU against ROS-and/or NO-induced endothelial cell injury will be discussed.

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Stimulation of nitric oxide synthase during oxidative endothelial cell injury

Cited by 34 publications

References 33 publications

Key role of PLC-γ in EGF protection of epithelial barrier against iNOS upregulation and F-actin nitration and disassembly

Key role of PLC-γ in EGF protection of epithelial barrier against iNOS upregulation and F-actin nitration and disassembly

Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity

Protective Effect of Tetrahydrobiopterin Against Reactive Oxygen Species- and Nitric Oxide-induced Vascular Endothelial Cell Injury

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