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Laboratory of Molecular Genetics, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
* To whom correspondence should be addressed. E-mail: mori-m{at}ph.sojo-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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10 mmol/L) are much higher than that of iNOS (5 µmol/L), whereas Vmax of arginase I and II were 103–104 times higher than that of iNOS in activated macrophages. Thus, Vmax/Km values of arginases were close to that of iNOS, and these enzymes were expected to compete for arginine in the cells. In fact, NO production by iNOS in activated macrophages was decreased by coinduction of arginase I or arginase II. Low concentrations of NO protect cells from apoptosis, whereas excessive NO causes apoptosis. We found that NO causes endoplasmic reticulum (ER) stress, induces a transcription factor, CAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), and leads to apoptosis. These results suggest that the arginine metabolic enzymes and the ER stress-CHOP pathway can be good targets to regulate NO production and NO-mediated apoptosis in diseases associated with overproduction or impaired production of NO.
Metabolism of arginine and NO
Arginine is synthesized from citrulline by successive actions of argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), the third and fourth enzymes of the urea cycle (ornithine cycle). The major site of arginine metabolism in ureotelic animals is the liver, where arginine generated in the urea cycle is rapidly converted to urea and ornithine by arginase with no net synthesis of arginine. Another major site is the kidney, where arginine is synthesized from citrulline and is released into the blood. However, many other tissues and cell types also contain low levels of AS and AL. In adult animals, citrulline is produced primarily by the small intestine from NH3, CO2, and ornithine by carbamylphosphate synthetase I and ornithine transcarbamylase, the first 2 enzymes of the urea cycle, and is supplied to the kidney and probably to other tissues for synthesis of arginine. Citrulline is also formed from arginine as a coproduct of NOS reaction, and this citrulline may be recycled to arginine if AS and AL are present in the same cell, forming the citrulline-NO cycle. In contrast, arginine is hydrolyzed to urea and ornithine by arginase. Thus, arginase and NOS use arginine as a common substrate and may compete with each other for this substrate.
NO production is up-regulated by the citrulline-NO cycle
Citrulline, a by-product of the NOS reaction, can be recycled to arginine by AS and AL in the citrulline-NO cycle. AS and AL are expressed strongly in the liver and kidney and at very low levels in many other tissues and cells. The citrulline-NO cycle was first shown to function in bovine aorta endothelial cells (2) and rat peritoneal macrophages (3). When iNOS is induced in various cells stimulated by bacterial LPS and cytokines, AS and sometimes AL are coinduced. Expression of iNOS, AS and AL in unstimulated and stimulated cells is summarized in Table 1. iNOS and AS were first found to be coinduced in immunostimulated murine macrophage-like RAW 264.7 cells (7), cultured rat aortic smooth muscle cells (10), and cultured rat and human pancreatic ß-cells (17). AL was not induced in these cells, probably because AS, not AL, is rate-limiting in the citrulline-arginine recycling reaction in many cells. Coinduction of iNOS and AS has also been shown in activated human tumor cell lines (20), rat glioma C6 cells (12,18), mouse microglial cells (10), and rat retinal pigment epithelial cells (16). NO was produced from citrulline (via arginine) as well as from arginine in activated C6 cells and retinal pigment epithelial cells, indicating that the citrulline-NO cycle is actually functioning in these cells (12,16). Surprisingly, when nerve growth factor-differentiated rat neuronal PC12 cells were immunostimulated, iNOS and AS were highly coinduced, and a large amount of NO was produced from citrulline and from arginine (14). The significance of this NO production in this neuronal cell remains to be studied.
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Decreased availability of arginine and impaired production of NO have been implicated in the development of endothelial dysfunction. However, we found that eNOS, AS, and AL are coinduced in the aorta in early stages of streptozotocin-induced diabetes in rats and that NO production is increased (11). Coinduction was also observed in human umbilical vein endothelial cells by transforming growth factor-ß1 (11). These results indicate that the citrulline-NO cycle operates in many cell types expressing iNOS and eNOS and up-regulates NO production.
Arginase isoforms
Arginase exists in 2 isoforms, liver-type arginase I and nonhepatic-type arginase II. Properties of these isoforms are summarized in Table 2. Arginase I is expressed almost exclusively in the cytosol of the liver cells under normal conditions and catalyzes the last step of urea synthesis. The enzyme was purified from livers of various mammals, and the crystal structure of the trimeric rat enzyme was revealed. cDNAs for the rat and human enzyme were isolated, and the predicted polypeptide chains are composed of 323 and 322 amino acid residues (23,24). The rat and human genes are 12-kbp and 11.5-kbp long, respectively, and consist of 8 exons (25,26). In the promoter region there are 2 binding sites for CCAAT/enhancer binding protein (C/EBP), 1 at position around –90 bp and the other around –55 bp (27,28). Binding of C/EBP family members to the region around –55 bp stimulates the promoter activity. Hepatocyte nuclear factor-4 (HNF-4) represses the promoter activity without directly binding the promoter region, and the region overlapping with the C/EBP binding site at 55 bp is responsible for the HNF-4 repression (28).
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-deficient mice, mRNA and protein levels for arginase I decrease markedly (29). Arginase I expression is induced in macrophages by Th2 cytokines such as IL-4 and IL-13. Pauleau et al. (30) and Gray et al. (31) showed that arginase I induction in mouse macrophages by IL-4 requires a responsive element containing STAT6 and C/EBPß sites located 3 kb upstream of the transcription start site. Arginase II is expressed in the mitochondrial matrix of nonhepatic tissues including the small intestine and kidney. The enzyme is also abundant in lactating mammary gland and is thought to be involved in proline synthesis. Human arginase II cDNA has been isolated (32–34). A polypeptide chain of 354 amino acid residues, including the putative NH2-terminal presequence for mitochondrial targeting and import, is predicted. Arginase II is 59% identical with arginase I. The mouse gene has been isolated (35). It contains 8 exons like the arginase I gene, and the exon-intron boundaries of the 2 isoform genes are similar, suggesting that these 2 genes arose by a gene duplication. Marathe et al. (36) found that arginase II is induced in macrophages by the liver X receptors (LXRs) that have been implicated in lipid metabolism and inflammation. They showed that the arginase II promoter contains a functional LXR-response element that mediates promoter induction by LXR/retinoid X receptor. This study suggests that the regulation of arginase II contributes to the immunomodulatory effects of LXRs.
NO production is down-regulated by arginase isoforms
Both NOS and arginase use arginine as a common substrate, and arginase may down-regulate NO production by competing with NOS for arginine. Expression of arginase isoforms in cells is summarized in Table 1. iNOS and arginase II are coinduced in LPS-stimulated RAW 264.7 macrophages (9,37). Surprisingly, however, we found that arginase I, not arginase II, is coinduced with iNOS in rat peritoneal macrophages and in vivo in rat lung after LPS treatment (4). In contrast, both arginase I and arginase II as well as iNOS are induced in LPS-activated mouse peritoneal macrophages (5,6); arginase II is induced early, whereas arginase I is induced much later. Because overproduction of NO is toxic to macrophages and neighboring cells, a mechanism to prevent overproduction of NO may exist. We speculate that arginase I is induced in the late stage of endotoxemia and prevents sustained overproduction of NO. Ochoa et al. (38) reported that arginase I is markedly induced in human mononuclear cells after injury, with a concomitant decrease of plasma concentrations of arginine and NO metabolites.
When RAW 264.7 cells are exposed to LPS and IFN-
, iNOS is induced, and NO production increases. When dexamethasone and dibutyryl cAMP are added, both iNOS and arginase II are induced, and NO production is much decreased (39). This means that induced arginase II down-regulates NO production by depleting intracellular arginine. Down-regulation of NO production by arginase was noted in the case of NO-mediated apoptosis. When RAW 264.7 cells are treated with LPS and IFN-, the cells undergo NO-dependent apoptosis (39). This apoptosis was prevented when arginase II was induced or expressed by cDNA transfection. Arginase I was also effective in preventing apoptosis. Thus, both cytosolic arginase I and mitochondrial arginase II are effective in down-regulating NO production and in preventing NO-mediated apoptosis in activated macrophages.
Vascular endothelial cells express iNOS and produce NO on stimulation with LPS and cytokines. Rat aortic endothelial cells contain both arginase isoforms, and LPS induced both iNOS and arginase II but not arginase I (40). Li et al. (41) prepared endothelial cells expressing arginase I or arginase II and demonstrated that both isoforms can down-regulate NO production. Hein et al. (42) studied the mechanism of the impairment of NO-dependent vasodilatation by ischemia-reperfusion and found that arginase activity is increased in arterioles of porcine heart after treatment and that NO production is decreased. An arginase inhibitor enhanced NO production and dilation in normal vessels and also restored the NO-mediated dilation after ischemia-reperfusion. Berkowitz et al. (43) reported that arginase decreases NO production in aortic rings from rats and that arginase up-regulation contributes to endothelial dysfunction of aging blood vessels. Therefore, arginase down-regulates NO production and may have important implications for cardiovascular function.
Low concentrations of NO protect cells from apoptosis
NO was reported to protect cultured hepatocytes from tumor necrosis factor--induced apoptosis by inducing heat shock protein 70 (Hsp70) (44). Therefore, we asked whether pretreatment of RAW 264.7 cells with a low dose of NO [0.1 mmol/L S-nitroso-N-acety1-N-DL-penicillamine (SNAP)] protects cells from apoptosis induced by a high dose of NO (1.5 mmol/L SNAP) (45). When cells were pretreated with 0.1 mmol/L SNAP for 3 h before 1.5 mmol/L SNAP treatment, apoptosis was prevented. Hsp70 was strongly induced by the pretreatment. Among DnaJ homologs, which act as cochaperones of Hsp70, DjB1 was strongly induced, and DjA1 was weakly induced; 1.5 mmol/L SNAP-induced apoptosis was prevented by coexpression of Hsp70 and DjB1 or DjA1. These results indicate that low concentrations of NO protect cells by inducing heat shock proteins.
NO-induced apoptosis is mediated by the ER stress pathway involving CHOP induction
Excess NO induces apoptosis in various cell types (1, 46–50). It is generally thought that NO induces DNA damage, leading to cell death through induction of p53. However, several experiments suggested that p53-independent signaling pathways operate during NO-mediated apoptosis. We analyzed the molecular mechanism of NO-mediated apoptosis in macrophages, microglia, and pancreatic ß-cells and found a new pathway, which is mediated by the endoplasmic reticulum (ER) stress pathway.
When RAW 264.7 cells were treated with LPS plus interferon- or the NO donor SNAP, NO-mediated apoptosis occurred (51). Under these conditions, p53 accumulation was not observed, indicating that DNA damage is not the main trigger of NO-mediated apoptosis. Furthermore, apoptosis was induced in p53-deficient MG5 microglial cells by exogenous and endogenous NO (52). We found that CHOP, a C/EBP family transcription factor that is involved in ER stress-induced apoptosis, is induced (53). BiP/GRP78, an ER chaperone that is known to be induced by ER stress, was also induced. Overexpression of CHOP in RAW 264.7 cells resulted in apoptosis. Peritoneal macrophages from CHOP-deficient mice were more resistant to NO-mediated apoptosis than those from wild-type animals. These results indicate that NO-induced apoptosis in macrophages and microglial cells is mediated by the ER stress pathway involving the induction of CHOP (Fig. 1).
Excessive NO production in cytokine-activated ß-cells has been implicated in ß-cell disruption in type 1 diabetes. ß-Cells are very vulnerable to NO-induced apoptosis. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6 ß-cells (53). mRNAs for p53 and its target genes p21 and GADD45 were not induced. In contrast, CHOP was induced by low concentrations of SNAP in MIN6 cells. SNAP increased cytosolic Ca2+, and only agents depleting ER Ca2+ induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca2+. Overexpression of calreticulin, a major Ca2+ binding protein in ER, increased the Ca2+ content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP-deficient mice showed resistance to NO-induced apoptosis. We conclude that NO depletes ER Ca2+, causes ER stress, and leads to apoptosis. Thus, ER Ca2+ stores are a newly recognized target of NO, and the ER stress pathway is a major mechanism of NO-mediated apoptosis in various cells, including macrophages, microglia, and pancreatic ß-cells.
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FOOTNOTES |
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2 Author disclosures: M. Mori, The International Council on Amino Acid Science paid for travel expenses to this meeting.
3 Supported by a Grant-in-Aid (No. 14037257) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
4 Abbreviations used: AL, argininosuccinate lyase; AS, argininosuccinate synthetase; C/EBP, CAAT/enhancer binding protein; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; HNF-4, hepatocyte nuclear factor-4; Hsp, heat shock protein; IFN-, interferon-; NGF, nerve growth factor; NO, nitric oxide; NOS, NO synthase; eNOS, endothelial NOS; iNOS, inducible NOS; nNOS, neuronal NOS; SNAP, S-nitroso-N-acetyl-DL-penicillamine.
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