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PubMed2004

Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles.

One characteristic of hypertension is a decreased endothelium-dependent nitric oxide (NO)-mediated vasodilation; however, the underlying mechanism is complex. In endothelial cells (ECs), L-arginine is the substrate for both NO synthase (NOS) and arginase. Because arginase has recently been shown to modulate NO-mediated dilation of coronary arterioles by reducing l-arginine availability, we hypothesized that upregulation of vascular arginase in hypertension contributes to decreased NO-mediated vasodilation. To test this hypothesis, hypertension (mean arterial blood pressure >150 mm Hg) was maintained for 8 weeks in pigs by aortic coarctation. Coronary arterioles from normotensive (NT) and hypertensive (HT) pigs were isolated and pressurized for in vitro study. NT vessels dilated dose-dependently to adenosine (partially mediated by endothelial release of NO) and sodium nitroprusside (endothelium-independent vasodilator). Conversely, HT vessels exhibited reduced dilation to adenosine but dilated normally to sodium nitroprusside. Adenosine-stimulated NO release was increased approximately 3-fold in NT vessels but was reduced in HT vessels. Moreover, arginase activity was 2-fold higher in HT vessels. Inhibition of arginase activity by N(omega)-hydroxy-nor-l-arginine or incubation with l-arginine partially restored NO release and dilation to adenosine in HT vessels. Immunohistochemistry showed that arginase expression was increased but NOS expression was decreased in arteriolar ECs of HT vessels. These results suggest that NO-mediated dilation of coronary arterioles is inhibited in hypertension by an increase in arginase activity in EC, which limits l-arginine availability to NOS for NO production. The inability of arginase blockade or l-arginine supplementation to completely restore vasodilation may be related to downregulation of endothelial NOS expression.

Animals↗

PubMed2005

Cytokine-induced endothelial arginase expression is dependent on epidermal growth factor receptor.

L-arginine is metabolized to nitric oxide (NO) by NO synthase (NOS), or to urea and L-ornithine by arginase. L-ornithine contributes to vascular remodeling in pulmonary hypertension via metabolism to polyamines and proline. Previously we found that cytokines upregulate both NOS and arginase in pulmonary arterial endothelial cells. We hypothesized that cytokine-induced arginase I and II expression depend on epidermal growth factor (EGF) receptor (EGFR) activity. Bovine pulmonary arterial endothelial cells were treated with lipopolysaccharide and tumor necrosis factor-alpha (L/T). L/T treatment resulted in a substantial increase in urea production, and this increase in urea production was potently inhibited by both genistein and AG1478, inhibitors of EGFR. Levels of arginase I protein and arginase II mRNA were increased in response to L/T treatment, and genistein prevented the L/T-induced elevations in both arginase I protein and arginase II mRNA levels. L/T treatment increased production of nitrites and inducible NOS mRNA accumulation, and genistein and AG1478 had little effect on these changes. EGF (50 ng/ml) treatment resulted in enhanced urea production. Finally, a 170-kD protein was phosphorylated upon treatment with either EGF or L/T. Our results indicate that arginase induction by L/T depends in part on EGFR activity. We speculate that EGFR inhibitors may attenuate vascular remodeling without affecting NO release, and thus may represent novel therapeutic modalities for pulmonary hypertensive disorders.

Animals↗

PubMed2007

Oxidative-nitrosative stress and post-translational protein modifications: implications to lung structure-function relations. Arginase modulates NF-kappaB activity via a nitric oxide-dependent mechanism.

NF-kappaB is a versatile transcription factor that regulates a wide array of processes, including inflammation and survival, and plays a critical role in the etiology of inflammatory lung diseases. Nitric oxide (NO) has been suggested to play an antiinflammatory role through S-nitrosation of components of NF-kappaB pathway. NO production can be modulated by changing the availability of its substrate, L-arginine. Arginases compete with NO synthases (NOSs) for their common substrate, L-arginine, and thereby have the potential to alter the signaling function of NO. The goal of the present study was to determine the impact of arginase manipulation on NO, and subsequent effects on NF-kappaB activation, in lung epithelial cells. Our results demonstrate that reduction of arginase activity enhanced cellular content of NO and S-nitrosated proteins, and resulted in decreases in TNF-alpha- or LPS-stimulated NF-kappaB DNA binding and transcriptional activity, in association with enhanced S-nitrosation of p50. The effects of arginase inhibition on NF-kappaB were reversed by the generic NOS inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), suggesting a causal role for NO in the attenuation of NF-kappaB induced by arginase suppression. Conversely, overexpression of arginase I decreased cellular S-nitrosothiol content and enhanced IkappaB kinase activity and NF-kappaB DNA binding, and decreased S-nitrosation of p50. Collectively, our data point to a regulatory mechanism wherein NF-kappaB is controlled through arginase-dependent regulation of NO levels, which may impact on chronic inflammatory diseases that are accompanied by NF-kappaB activation and upregulation of arginases.

Animals↗

PubMed2004

Dogmas and controversies in the handling of nitrogenous wastes: expression of arginase Type I and II genes in rainbow trout: influence of fasting on liver enzyme activity and mRNA levels in juveniles.

Through analysis of a cDNA library and third-party annotation of available database sequences, we characterized the full-length coding regions of rainbow trout (Oncorhynchus mykiss) Type I, Onmy-ARG01, and Type II, Onmy-ARG02, arginase genes. Two partial related arginase sequences, Onmy-ARG01b and Onmy-ARG02b, and a full-length zebrafish arginase coding region (Danio rerio), Dare-ARG02, are also reported. Comparison of vertebrate arginase sequences shows that both Type I and Type II genes in bony fishes contain a mitochondrial targeting N-terminal domain. This suggests that the cytosolic Type I arginase found in ureotelic vertebrates arose in the common ancestor of amphibia and mammals. Onmy-ARG01 and Onmy-ARG02 mRNA was detected in liver, kidney, gill, intestine, red muscle and heart tissues. Onmy-ARG01 was expressed at a significantly higher level relative to Onmy-ARG02 in liver and red muscle tissue. To investigate whether there was differential regulation of Onmy-ARG01 and Onmy-ARG02, juvenile trout were fasted for 6 weeks and hepatic enzyme activities and mRNA levels were compared with those of fed control fish. There was a 3-fold increase in liver arginase activity and a 2-fold increase in Onmy-ARG02 mRNA levels but no change in Onmy-ARG01 mRNA levels in fasted fish relative to fed fish. These findings indicate that both types of arginase genes are present and expressed in rainbow trout and that the pattern of expression varies between tissues. The increase in liver arginase activity after a 6-week fast is due, in part, to an increase in the expression of Onmy-ARG02 mRNA levels.

Amino Acid Sequence↗

PubMed2004

Relationship among manganese, arginase, and nitric oxide in childhood asthma.

It has been demonstrated that the lowest intakes of manganese (Mn) were associated with more than a fivefold increased risk of bronchial reactivity. It was also known that nitric oxide (NO) production was found to be significantly higher in asthmatics. There is a reciprocal pathway between arginase and nitric oxide synthase (NOS) for NO production, and Mn is required for arginase activity and stability. We investigated plasma NO, arginase, and its cofactor Mn levels to evaluate this reciprocal pathway in patients with childhood asthma. Arginase activities and Mn and NO levels were measured in plasma from 31 patients with childhood asthma and 22 healthy control subjects. Plasma arginase activities and Mn concentrations were found to be significantly lower and NO levels were significantly higher in patients with childhood asthma as compared to the control subjects. There was a significantly positive correlation between plasma Mn and arginase and negative correlations between arginase and NO values and Mn and NO values in patients with childhood asthma. These data indicate that the lower concentration of Mn could cause lower arginase activity and this could also upregulate NO production by increasing l-arginine content in patients with childhood asthma.

Adolescent↗

PubMed1999

Autoantibody to the liver arginase present in sera of patients with autoimmune hepatitis and chronic hepatitis.

We have reported previously that immunization of rat liver arginase in rabbits induced autoantibody that is reactive with their own liver arginase and has cytotoxic activity to their hepatocytes. This promoted us to investigate whether or not such an autoantibody is present in sera of patients with certain hepatic disorders, since the liver arginase is dominant in the liver and highly homologous in structure among ureotelic animals. By Western blot analysis, sera from patients with chronic hepatitis and autoimmune hepatitis were shown to have an autoantibody reacting with purified human liver arginase. Since the autoantibody was also reactive with liver arginase of rat origin to almost the same extent as that of human origin, ELISA with rat liver arginase as a coating antigen was developed and used for the quantification of the autoantibody. Prominent increase of the anti-liver arginase autoantibody was found in autoimmune hepatitis, moderate increase in chronic liver diseases, and no increase in acute hepatitis or normal controls by the ELISA. These results suggest that the increased anti-liver arginase autoantibody might involve in some parts in the pathophysiology of the hepatitic disorders. Assay of the autoantibody can also be utilized as a marker for the differentiation of certain hepatitis.

Adolescent↗

PubMed2002

Helicobacter pylori induces macrophage apoptosis by activation of arginase II.

Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting L-arginine to L-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-kappa B-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors N(omega)-hydroxy-L-arginine or N(omega)-hydroxy-nor-L-arginine, but not by the iNOS inhibitor N-iminoethyl-L-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes L-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase II expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.

Animals↗

PubMed2004

Protective role of arginase in a mouse model of colitis.

Arginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginine (Arg). Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines. We investigated the role of these enzymes in the Citrobacter rodentium model of colitis. Arginase I, iNOS, and ODC were induced in the colon during the infection, while arginase II was not up-regulated. l-Arg supplementation of wild-type mice or iNOS deletion significantly improved colitis, and l-Arg treatment of iNOS(-/-) mice led to an additive improvement. There was a significant induction of IFN-gamma, IL-1, and TNF-alpha mRNA expression in colitis tissues that was markedly attenuated with l-Arg treatment or iNOS deletion. Treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine worsened colitis in both wild-type and iNOS(-/-) mice. Polyamine levels were increased in colitis tissues, and were further increased by l-Arg. In addition, in vivo inhibition of ODC with alpha-difluoromethylornithine also exacerbated the colitis. Taken together, these data indicate that arginase is protective in C. rodentium colitis by enhancing the generation of polyamines in addition to competitive inhibition of iNOS. Modulation of the balance of iNOS and arginase, and of the arginase-ODC metabolic pathway may represent a new strategy for regulating intestinal inflammation.

Animals↗

PubMed2006

Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness.

Increased arginase I activity is associated with allergic disorders such as asthma. How arginase I contributes to and is regulated by allergic inflammatory processes remains unknown. CD4+ Th2 lymphocytes (Th2 cells) and IL-13 are two crucial immune regulators that use STAT6-dependent pathways to induce allergic airways inflammation and enhanced airways responsiveness to spasmogens (airways hyperresponsiveness (AHR)). This pathway is also used to activate arginase I in isolated cells and in hepatic infection with helminths. In the present study, we show that arginase I expression is also regulated in the lung in a STAT6-dependent manner by Th2-induced allergic inflammation or by IL-13 alone. IL-13-induced expression of arginase I correlated directly with increased synthesis of urea and with reduced synthesis of NO. Expression of arginase I, but not eosinophilia or mucus hypersecretion, temporally correlated with the development, persistence, and resolution of IL-13-induced AHR. Pharmacological supplementation with l-arginine or with NO donors amplified or attenuated IL-13-induced AHR, respectively. Moreover, inducing loss of function of arginase I specifically in the lung by using RNA interference abrogated the development of IL-13-induced AHR. These data suggest an important role for metabolism of l-arginine by arginase I in the modulation of IL-13-induced AHR and identify a potential pathway distal to cytokine receptor interactions for the control of IL-13-mediated bronchoconstriction in asthma.

Animals↗

PubMed2001

[Clinical significance of anti-liver-type arginase autoantibody in blood of recipients after partial liver transplantation].

Autoantibody against human liver-type arginase was detected in blood of patients treated with partial liver transplantation and consisted of all subclasses of IgG, i.e., IgG1, IgG2, IgG3 and IgG4, and IgM. We newly constructed an ELISA system for the antibodies by the aid of arginase protein immunopurified from extracts of human liver tissues. Addition of 2.0 mol/l urea in 0.1 mol/l citrate buffer(pH 4.5) was effective for elimination of immunoglobulins, such as IgG and IgM, and rheumatoid factors adsorped non-specifically to liver-type arginase-autoantibody complexes on the plate. We found that, during a short period of about two months after operation, in successful cases, liver-type arginase increased, remarkably and repeatedly, in blood of recipients followed by elevation of IgM level within a week and also IgG2 level two or three weeks later. Thus the change in IgG2 level seemed to depend on those of the arginase and/or IgM. However, in unsuccessful cases, such fluctuation was not so clear as the successful cases. To be noteworthy was production of autoantibodies directed to liver-type arginase in blood of patients with liver injury although the arginase, as well as AST and ALT, is an enzyme which leaks out of liver tissue. Appearance of the autoantibodies in blood supports occurrence of liver injury, in part, in graft liver because the enzyme exists exclusively in the liver. Among immunoglobulins to liver-type arginase, IgG2 seemed to be the most helpful index to know rightly postoperative conditions of recipients of liver transplantation, and its measurement could be useful for long-term follow-up of the patients.

Arginase↗

PubMed2002

Biochemical characterization of the arginine degrading enzymes arginase and arginine deiminase and their effect on nitric oxide production.

BACKGROUND: Nitric oxide (NO) is a biomediator believed to be synthesized primarily from extracellular arginine. Various methodologies have been used to inhibit NO synthesis so as to elucidate its physiological and pathophysiological functions. Several investigators have utilized various argin ine degrading enzymes as a means of lowering extracellular arginine. Arginase, most commonly derived from mammalian sources, has been most often used. However, arginase has failed to inhibit NO synthesis. Therefore, a systematic biochemical characterization of arginase and arginine deiminase (ADI) derived from M. Hominus was undertaken. MATERIAL/METHODS: The murine macrophage cell line N-9 was treated with either arginase or arginine deiminase to determine the effect on intracellular and extracellular arginine and nitric oxide production. RESULTS: Arginase was found to have an alkaline pH optima(approximately 9.5) with little enzyme activity at physiological pH. In contrast, the pH optima of ADI was approximately 6.5, retaining >70% of its activity at physiological pH. ADI had more than 1000 fold higher affinity for arginine (Km approximately 30 KM for ADI vs approximately 45 mM for arginase), and was able to lower arginine levels to a much greater extent than arginase. ADI, unlike arginase, was effective in lowering extracellular arginine in tissue culture media and inhibit NO production by the murine macrophage cell line N-9 in response to gamma interferon and LPS stimulation. CONCLUSIONS: These data suggest that ADI may be useful for delineating the role of NO in a variety of biological systems as well as determining the role of extracellular arginine in its synthesis.

Animals↗

PubMed2002

[Arginase a marker of cancerogenesis. II. Monitoring of patients after resection of colorectal liver metastases].

Preoperative activity of arginase in blood serum of patients with colorectal cancer metastases to the liver is much higher than in serum of healthy blood donors. Before tumour resection in serum of 100 patients two cut-off levels of arginase activity were observed--in 65 subjects the activity ranged from 10 to 70 U/(group I), and in 35 subjects (group II), from 100 to 200 U/l. The raised arginase activity was observed in 83% of patients from group I, and in all studied patients (100%) from subgroup II. After liver surgery, arginase activity decreased to the normal value in the majority of patients. During three years of surveillance, in 88% and 63% of patients from either subgroup, respectively, no significant increase in arginase activity was observed, and the patients remained cancer-free. However, the rise of arginase activity was demonstrated in 13% and 37% subjects from either subgroup, respectively--the patients developed second liver metastases or died. Metastases and deaths were observed more often in patients from group II than I. The rise in arginase activity in blood serum after resection of colorectal cancer metastases to the liver indicates the possibility of new cancerogenesis. The special group at risk are patients with high (100 or more U/l) preoperative serum arginase activity.

Adult↗

PubMed2003

Arginine deprivation and tumour cell death: arginase and its inhibition.

Arginase treatment of cell cultures reduced arginine in the medium to approximately micromolar levels within 5-30 min, and proved as effective as arginine-free medium (AFM) prepared by formulation. The enzyme was heat stable and as active at pH 7.2 as at pH 9.9. It persisted in culture for at least 3 days with only a small diminution in its speed of action, and still actively destroyed arginine after 6 days, since arginine supplementation failed to rescue viable cells. Addition of L-norvaline, an inhibitor of arginase, rescued cells from arginase-induced deprivation. Its efficacy at low concentrations was short-lived (probably < 1 day), while at higher concentrations it did not appear to inhibit completely the enzyme. However, L-norvaline at these same levels also slowed the growth of positive non-enzyme treated controls receiving the normal arginine level. Thus the difference in this growth indicated that arginase was more inhibitory than cursory examination of initial kinetic data suggested. It also agreed with the inhibition of arginase in the ornithine assay used to measure biochemically enzyme activity. We conclude that norvaline partially but not completely antagonises arginase activity, which allows cell rescue in a dose-dependent manner between 0.4 and 4 mM, but cannot be used above about 2 mM without exhibiting a general non-specific interference of cell growth of its own, although no evidence of cell toxicity was observed in either AFM or arginine-containing medium. L-ornithine, the product of arginase that inhibits the enzyme by a feedback mechanism, had no inhibitory effect on arginase over a similar concentration range.

Animals↗

PubMed1995

Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity.

Macrophage arginine metabolism via nitric oxide (NO) synthase and arginase pathways reduces and enhances tumor cell proliferation, respectively. Transforming growth factor-beta (TGF-beta) has been shown to down-regulate the NO synthase pathway. The present study describes the effect of TGF-beta on the arginase pathway. TGF-beta up-regulated arginase activity in rat peritoneal macrophages as assessed by measuring the generation of [14C]urea from [14C]-L-arginine in the presence of NG-monomethyl-L-arginine (L-NMMA). The stimulation, which reached fivefold after a 48-h exposure of macrophages to 10 ng/ml TGF-beta, was due to reduction in Km value of arginase. TGF-beta-induced up-regulation of arginase activity led to the release of more polyamines, mainly putrescine. The role of this up-regulation on macrophage cytotoxicity toward L-929 tumor cells was analyzed in coculture experiments. Macrophages blunted DNA synthesis by L-929 cells as assessed by measuring the incorporation of [3H]TdR into the cells and the proportion of cells in the G2 phase. Addition of TGF-beta in the presence of L-NMMA permitted L-929 cells cocultured with macrophages to resume DNA synthesis. The mechanism responsible for this restoration was the up-regulation of arginase activity rather than the down-regulation of NO synthase activity since TGF-beta in the presence of L-NMMA failed to further reduce NO synthase activity whereas it still enhanced arginase activity; synthetic putrescine (1-10 microM) also blunted macrophage cytotoxicity toward L-929 cells. This is the first evidence that TGF-beta up-regulates arginase activity in macrophages and, hence, limits macrophage-dependent cytostasis.

Animals↗

PubMed2003

Effects of dietary vitamin E and selenium on arginase activity in the liver, kidneys, and heart of rats treated with high doses of glucocorticoid.

The effects of dietary intake of vitamin E and selenium on arginase activity in the liver, kidneys, and heart of rats treated with high doses of prednisolone were investigated. Rats were divided into five groups. Groups 3, 4, and 5 received a daily supplement in their drinking water of vitamin E, Se, and a combination of vitamin E and Se, respectively, for 30 days. For 3 days subsequently, the control group (group 1) was given a placebo, and the remaining four groups were injected intramuscularly with prednisolone. The tissue samples were collected from each group at 4, 8, 12, 24, and 48 h after the last administration of prednisolone. In the group treated with prednisolone alone, arginase activity in the liver was found to have increased at all the time periods, whereas it had decreased significantly in the heart at 48 h. Arginase activity in the kidneys was not affected by prednisolone. Compared to the control and prednisolone groups, arginase activity in the kidneys and heart of the vitamin E- and Se-supplemented groups was found to be significantly increased at all time periods, however, no difference was seen in the combination group. Arginase activity in the liver of the vitamin E-supplemented group was found to have decreased at all time periods, however, in the Se group compared to the prednisolone group it had reduced at 24 and 48 h only. In the combination group compared to the prednisolone group, liver arginase activity increased constantly up to 12 h returning to normal values at 48 h. Vitamin E and Se in combination may prevent the changes in arginase activity in various tissues caused by prednisolone.

Animal Feed↗

PubMed2003

Nitric oxide synthase and arginase in the rat hippocampus and the entorhinal, perirhinal, postrhinal, and temporal cortices: regional variations and age-related changes.

Increasing evidence suggests that nitric oxide synthase (NOS)/nitric oxide (NO) contributes to the aging process. By contrast, the role of arginase, which shares a common substrate with NOS, has not been determined. In the present study, regional variations and age-related changes in NOS and arginase in the hippocampus and its neighboring structures were investigated for the first time. In young adult rats, high levels of NOS activity were found in the entorhinal, perirhinal, and postrhinal cortices, whereas low values were located in the hippocampus and the temporal cortex. Interestingly, arginase activity showed an overall inverse pattern with the lowest levels in the entorhinal and perirhinal cortices. When a comparison was carried out between young (4-month-old) and aged (24-month-old) rats, significant increases in total NOS activity were found in the aged entorhinal and temporal cortices, and a significant decrease in arginase activity was observed in the aged postrhinal cortex. Western blotting demonstrated significant decreases in both neuronal and endothelial NOS expression in the aged hippocampus and postrhinal cortex, whereas arginase I and II expression did not show age-related changes in any region examined. Activity and protein expression of inducible NOS were not detected in any tissue from either group. The present findings of region-specific changes in NOS and arginase appear to support the potential involvement of NOS/NO in the aging process and raise the issue of a possible contribution of arginase to aging.

Aging↗

PubMed1982

Molecular cloning, DNA structure, and RNA analysis of the arginase gene in Saccharomyces cerevisiae. A study of cis-dominant regulatory mutations.

The Saccharomyces cerevisiae gene cargA + or CAR1 , encoding arginase has been cloned by recovering function in transformed yeast cells. It was used to analyse RNA and chromosomal DNA from six strains bearing cis-dominant regulatory mutations leading to constitutive arginase synthesis. The DNA from the four cargA + O- strains in which constitutive arginase synthesis was independent of the mating-type functions showed no detectable differences with the wild- typye . The cargA + O- mutations were, therefore, small alterations, possibly single base substitutions. On the other hand, the cargA + Oh-1 and cargA + Oh-2 mutations, leading to a constitutive and mating-type dependent arginase synthesis, were identified as insertions. Their size and restriction pattern strongly suggested that they were induced by the Ty1 yeast transposable element. This was confirmed by cloning and analysis of the cargA + Oh-1 mutant gene. The concentration of arginase RNA was significantly increased in the mutants, indicating that the regulation of arginase synthesis was exerted, at least in part, at the level of RNA synthesis or stability. In the cargA + Oh-2 strain the Ty1 element was located at a distance of approximately 600 base pairs from the insertion present in the cargA + Oh-1 strain. This result suggests either a surprisingly large arginase regulatory region or an indirect influence of the Ty1 element on gene expression over long distances.

Arginase↗

PubMed2000

Induction of arginase II in human Caco-2 tumor cells by cyclic AMP.

The objective of this study was to elucidate the mechanism by which cyclic AMP increases arginase activity in cultured human Caco-2 tumor cells. Caco-2 cells were incubated for 24 h in the presence of 8-bromo cyclic AMP or forskolin, and the cells were harvested, lysed, and assayed for total arginase activity. Both test agents increased arginase activity by twofold, and this was attributed to the induction of the arginase II isoform. Both arginase II mRNA and protein showed increased expression in response to 8-bromo cyclic AMP and forskolin, and these effects were inhibited by H-89 (protein kinase A inhibitor), enhanced by okadaic acid (phosphatase inhibitor), and enhanced by 1-methyl-3-isobutylxanthine (cyclic nucleotide phosphodiesterase inhibitor). Cyclic GMP did not appear to be involved in arginase II induction. These observations indicate that cyclic AMP stimulates arginase II gene expression by mechanisms involving activation of protein kinase A and consequent activation of appropriate transcription factors.

1-Methyl-3-isobutylxanthine↗