Induction of citrulline–nitric oxide (NO) cycle enzymes and NO production in immunostimulated rat RPE-J cells

Koga, Toshikatsu; Zhang, Wen Yi; Gotoh, Tomomi; Oyadomari, Seiichi; Tanihara, Hidenobu; Mori, Masataka

doi:10.1016/s0014-4835(02)00274-9

Cited by 22 publications

(8 citation statements)

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“…In addition, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), a product of COX-2, is a well-established Nrf2 activator [71]. Nonetheless, as stated above, this is speculation as many other NF-κB-regulated proteins including NADPH oxidase 4 [72] and iNOS [73] that produce oxidants may also activate Nrf2 through direct oxidation of Keap1 cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Zhang

Zhou

Yuen

et al. 2017

Free Radical Biology and Medicine

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Silica nanoparticles with iron on their surface cause the production of oxidants and stimulate an inflammatory response in macrophages. Nuclear factor erythroid-derived 2 –like factor 2 (Nrf2) signaling and its regulated antioxidant genes play critical roles in maintaining redox homeostasis. In this study we investigated the regulation of four representative Nrf2-regulated antioxidant genes; i.e., glutamate cysteine ligase (GCL) catalytic subunit (GCLC), GCL modifier subunit (GCLM), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1), by iron-coated silica nanoparticles (SiO2-Fe) in human THP-1 macrophages. We found that the expression of these four antioxidant genes was modified by SiO2-Fe in a time-dependent manner. At 6 h, their expression was unchanged except for GCLC, which was reduced compared with controls. At 18 h, the expression of these antioxidant genes was significantly increased compared with controls. In contrast, the Nrf2 activator sulforaphane induced all antioxidant genes at as early as 3 h. The nuclear translocation of Nrf2 occurred later than that for NF-κB p65 protein and the induction of proinflammatory cytokines (TNFα and IL-1β). NF-κB inhibitor SN50 prevented the reduction of GCLC at 6 h and abolished the induction of antioxidant genes at 18 h by SiO2-Fe, but did not affect the basal and sulforaphane-induced expression of antioxidant genes, suggesting that NF-κB signaling plays a key role in the induction of Nrf2-mediated genes in response to SiO2-Fe. Consistently, SN50 inhibited the nuclear translocation of Nrf2 caused by SiO2-Fe. In addition, Nrf2 silencing decreased the basal and SiO2-induced expression of the four reprehensive antioxidant genes. Taken together, these data indicated that SiO2-Fe induced a delayed response of Nrf2-regulated antioxidant genes, likely through NF-κB-Nrf2 interactions.

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Section: Discussionmentioning

confidence: 99%

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Zhang

Zhou

Yuen

et al. 2017

Free Radical Biology and Medicine

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“…Then, coinduction of iNOS and ASS was demonstrated in vivo in various tissues including heart, kidney, lung and spleen by using LPS-treated rats [118,119]. Such a coinduction was also obtained in various LPS-and/or cytokine-stimulated cells in culture [14,17,18] including different cell lines [20,21,120] and different kind of cells of the nervous system [121][122][123]. In neurones and glial cells of rodent and human brains [121][122][123][124][125][126], both iNOS and ASS were shown to be increased by LPS and/or cytokines, but some cells in the nervous system did not express both enzymes, suggesting the existence of an intercellular citrulline-NO cycle [7,126].…”

Section: Ass a Potential Limiting Step In No Productionmentioning

confidence: 99%

Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle

Husson¹,

Brasse‐Lagnel²,

Fairand³

et al. 2003

European Journal of Biochemistry

282

239

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Argininosuccinate synthetase (ASS, EC 6.3.4.5) catalyses the condensation of citrulline and aspartate to form argininosuccinate, the immediate precursor of arginine. First identified in the liver as the limiting enzyme of the urea cycle, ASS is now recognized as a ubiquitous enzyme in mammalian tissues. Indeed, discovery of the citrulline–NO cycle has increased interest in this enzyme that was found to represent a potential limiting step in NO synthesis. Depending on arginine utilization, location and regulation of ASS are quite different. In the liver, where arginine is hydrolyzed to form urea and ornithine, the ASS gene is highly expressed, and hormones and nutrients constitute the major regulating factors: (a) glucocorticoids, glucagon and insulin, particularly, control the expression of this gene both during development and adult life; (b) dietary protein intake stimulates ASS gene expression, with a particular efficiency of specific amino acids like glutamine. In contrast, in NO‐producing cells, where arginine is the direct substrate in the NO synthesis, ASS gene is expressed at a low level and in this way, proinflammatory signals constitute the main factors of regulation of the gene expression. In most cases, regulation of ASS gene expression is exerted at a transcriptional level, but molecular mechanisms are still poorly understood.

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“…Although our studies focused on the role of recycling for endothelial NO production by eNOS, previous studies have demonstrated the importance of recycling for NO production by both iNOS and nNOS (39 -49). For example, AS and inducible NOS are coinduced in immunostimulated macrophages (39,40) as well as in stimulated RPE-J cells where the citrulline-NO cycle is shown to be functioning (41). In addition, coinduction of iNOS, CAT-2, and AS in rat microglial cells indicates that both arginine transport by CAT-2 and citrulline-arginine recycling are important in the production of large amounts of NO in activated microglial cells (42).…”

Section: Table Imentioning

confidence: 99%

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Goodwin

Solomonson

Eichler

2004

Journal of Biological Chemistry

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Although cellular levels of arginine greatly exceed the apparent K m for endothelial nitric-oxide synthase, current evidence suggests that the bulk of this arginine may not be available for nitric oxide (NO) production. We propose that arginine regeneration, that is the recycling of citrulline back to arginine, defines the essential source of arginine for NO production. To support this proposal, RNA interference analysis was used to selectively reduce the expression of argininosuccinate synthase (AS), because the only known metabolic role for AS in endothelial cells is in the regeneration of L-arginine from L-citrulline. Western blot analysis demonstrated a significant and dose-dependent reduction of AS protein as a result of AS small interfering RNA treatment with a corresponding diminished capacity to produce basal or stimulated levels of NO, despite saturating levels of arginine in the medium. Unanticipated, however, was the finding that the viability of AS small interfering RNA-treated endothelial cells was significantly decreased when compared with control cells. Trypan blue exclusion analysis suggested that the loss of viability was not because of necrosis. Two indicators, reduced expression of Bcl-2 and an increase in caspase activity, which correlated directly with reduced expression of AS, suggested that the loss of viability was because of apoptosis. The exposure of cells to an NO donor prevented apoptosis associated with reduced AS expression. Overall, these results demonstrate the essential role of AS for endothelial NO production and cell viability.Nitric oxide (NO) 1 is an important modulator for a wide range of functions including vasodilation of blood vessels, immune system function, angiogenesis, inhibition of leukocyte adhesion and platelet aggregation, gene regulation, and apoptosis (1-3). Moreover, NO has a dual role in cell viability depending on the tissue type and concentration. Either very high or very low concentrations of NO may induce cell death, whereas basal concentrations may inhibit apoptosis (4 -7). Previous work has shown that NO protects against serum starvation-(8), H 2 O 2 -(9), TNF-␣-(10), and oxidized low density lipoprotein-induced apoptosis (11, 12) in endothelial cells.Argininosuccinate synthase (AS), the rate-limiting step (13) in the regeneration of arginine from citrulline, catalyzes the synthesis of argininosuccinate, AMP, and inorganic pyrophosphate from citrulline, ATP, and aspartate. Argininosuccinate is then cleaved by argininosuccinate lyase (AL) to produce Larginine and fumarate. In the liver, AS and AL function together as components of the urea cycle, ultimately to form arginine from citrulline. Although the expression of AS and AL in the liver is high, both enzymes are found in most mammalian tissues, although at significantly lower levels. The discovery of arginine-derived NO, catalyzed by nitric-oxide synthases (NOSs), revealed a second role for AS and AL (1-3). Together with NOS, they function as part of a citrulline-NO cycle where AS and AL convert citrul...

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Induction of citrulline–nitric oxide (NO) cycle enzymes and NO production in immunostimulated rat RPE-J cells

Cited by 22 publications

References 50 publications

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Delayed Nrf2-regulated antioxidant gene induction in response to silica nanoparticles

Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

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