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PubMed1979

Preparation of a non-immunogenic arginase by the covalent attachment of polyethylene glycol.

Methoxypolyethylene glycol of 5000 daltons (PEG) was attached covalently to bovine liver arginase using 2,4,6-trichloro-s-triazine as the coupling agent. The conjugate (PEG-arginase), with PEG attached to 53% of the amino groups, retained 65% of its original enzymatic activity. Mice were injected intravenously with arginase or PEG-arginase for periods of one to three months. The blood-circulating life of PEG-arginase was greatly extended over that of arginase. The half-life of injected arginase at day 30 was less than 1 h, whereas that of the PEG-enzyme was 12 h. Antisera from mice injected with native arginase reacted against arginase but not against PEG-arginase when tested by immunodiffusion. Antisera from animals injected with PEG-arginase reacted neither with native arginase nor PEG-arginase. The data indicate that arginase modified by PEG has been rendered both non-immunogenic and non-antigenic when tested in mice. The injection of PEG-arginase into mice did not induce tolerance toward the native enzyme. Injected PEG-arginase, in the presence of precipitating antibody directed against native arginase, circulated at the same level as in virgin animals. The attachment of PEG to arginase altered its kinetic properties.

Animals↗
PubMed1998

Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells.

Activated macrophages avidly consume arginine via the action of inducible nitric oxide synthase (iNOS) and/or arginase. In contrast to our knowledge regarding macrophage iNOS expression, the stimuli and mechanisms that regulate expression of the cytosolic type I (arginase I) or mitochondrial type II (arginase II) isoforms of arginase in macrophages are poorly defined. We show that one or both arginase isoforms may be induced in the RAW 264.7 murine macrophage cell line and that arginase expression is regulated independently of iNOS expression. For example, 8-bromo-cAMP strongly induced both arginase I and II mRNAs but not iNOS. Whereas interferon-gamma induced iNOS but not arginase, 8-bromo-cAMP and interferon-gamma mutually antagonized induction of iNOS and arginase I mRNAs. Dexamethasone, which did not induce either arginase or iNOS, almost completely abolished induction of arginase I mRNA by 8-bromo-cAMP but enhanced induction of arginase II mRNA. Lipopolysaccharide (LPS) induced arginase II mRNA, but 8-bromo-cAMP plus LPS resulted in synergistic induction of both arginase I and II mRNAs. In all cases, increases in arginase mRNAs were sufficient to account for the increases in arginase activity. These complex patterns of expression suggest that the arginase isoforms may play distinct, although partially overlapping, functional roles in macrophage arginine metabolism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2006

Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling.

Oxidized low-density lipoprotein (OxLDL) impairs NO signaling and endothelial function, and contributes to the pathogenesis of atherosclerosis. Arginase reciprocally regulates NO levels in endothelial cells by competing with NO synthase for the substrate l-arginine. In human aortic endothelial cells, OxLDL stimulation increased arginase enzyme activity in a time- and dose-dependent manner. Arginase activity reached its maximum as early as 5 minutes, was maintained for a period of more than 48 hours, and was associated with a reciprocal decrease in NO metabolite (NOx [nitrite and nitrate]) production. Furthermore, OxLDL induced arginase II mRNA expression after 4 hours. Small interfering RNA targeted to arginase II decreased both the quantity and the activity of arginase from baseline, prevented OxLDL-dependent increases in arginase activity, and induced an increase in NOx production. Immunofluorescence analysis revealed an association of arginase II with the microtubule cytoskeleton. Microtubule disruption with nocodazole caused a dramatic redistribution of arginase II to a diffuse cytosolic pattern, increased arginase activity, and decreased NOx production, which was restored in the presence of the specific arginase inhibitor (S)-(2-boronoethyl)-l-cysteine (BEC). On the other hand, epothilone B prevented microtubule disruption and inhibited OxLDL-dependent increases in arginase activity and attenuated OxLDL-dependent decreases in NOx. Preincubation of rat aortic rings with OxLDL resulted in an increase in arginase activity and a decrease in NOx production. This was reversed by arginase inhibition with the BEC. Thus, OxLDLs increase arginase activity by a sequence of regulatory events that involve early activation through decreased association with microtubules and a later increase in transcription. Furthermore, increased arginase activity contributes to OxLDL-dependent impairment of NOx production. Arginase, therefore, represents a novel target for therapy in atherosclerosis.

Animals↗
PubMedDate not supplied

[Arginase activity in plasma and erythrocytes in children with hematologic diseases].

INTRODUCTION: Arginase (EC 3.5.3.1) is one of the essential enzymes in the terminal stages of the urea cycle in the liver which participates in the elimination of ammonia from the human body [1, 7]. Except in liver tissue arginase is also present in many human tissues and in the circulating blood cells, especially in erythrocytes and leukocytes. Arginase splits arginase to urea and ornithine that serve for biosynthesis of amino acid proline, glutamic acid and biosynthesis of polyamines-spermine, spermidine and putrescine. Arginase activity is high during the mitotic cycle, with the function in phase S of the cell cycle. The aim of our study was to assess the arginase activity in the blood of children with some haematologic diseases. METHODS: We examined the arginase activity in blood plasma and erythrocytes of children who suffer from some haematological disorders (27 patients) and in healthy children (control group-15 subjects). The enzyme activity was measured with spectrophotometric method on the basis of the determination of the amount of liberated ornithine from substrate-arginine [3]. RESULTS: The obtained results suggest that arginase activity was much higher in the blood of ill children (Table 1 and Figure 1). In the control group of children (total 15) plasma arginase activity was in the range of 0 to 20 U/L x = 0.86 U/L), and enzyme activity in erythrocytes was 1.62-3.98 U/g Hb (x = 2.81 U/g Hb). Erythrocytes enzyme activity and plasma enzyme activity were in ranges of 4.03-5.26 U/L with the mean value of x = 4.56 U/L, and arginase activity in erythrocytes was in ranges of 9.38-14.16 U/g Hb, with mean value x = 11.34 U/g Hb, respectively. Arginase activity in erythrocytes was also significantly higher in children with non-spherocytic haemolytic anaemia (9 children) and was in ranges of 5.33-9.58 U/g Hb (x = 7.29 U/g Hb), with the relatively low values in plasma, 0-4.14 U/L (x = 1.75 U/L). In children with sideropenic anaemia (total number-11) arginase activity in erythrocytes was also very significantly increased with the range between 2.86 and 14.16 U/g Hb (x = 5.54 U/g Hb) while the plasma enzyme activity was relatively low, with the values in range of 0-4.98 U/L (x = 1.41 U/L); in myelodysplastic syndrome (4 pts) arginase activity in plasma was very low (0-0.71 U/L; x = 0.26 U/L) with higher values of arginase activity in erythrocytes (4.22-5.89 U/g Hb; x = 4.94 U/g Hb). DISCUSSION: We have concluded that the enzyme activity was the highest in erythrocyte haemolysates of patients with spherocytosis, non-sherocytic haemolytic anaemia; it was also high, but in a smaller degree, in erythrocytes of children with sideropenic anaemia and myelodysplastic syndrome; arginase activity in plasma of these children was higher in comparison with enzyme activity in plasma and erythrocytes of healthy children. Our results are in agreement with data from literature where it is stated that the younger erythrocytes have the highest arginase activity than the mature erythrocytes [4]. CONCLUSION: The measurement of arginase activity in plasma and erythrocytes is a good diagnostic indicator for the presence of young erythrocytes and reticulocytes in the circulating blood as is the good sign for the detection of haemolytic processes.

Anemia↗
PubMed2006

Time course of vascular arginase expression and activity in spontaneously hypertensive rats.

There is growing evidence that vascular arginase plays a role in pathophysiology of vascular diseases. We recently reported high arginase activity/expression in young adult hypertensive spontaneously hypertensive rats (SHR). The aim of the present study was to characterize the time course of arginase pathway abnormalities in SHR and to explore the contributing role of hemodynamics and inflammation. Experiments were conducted on 5, 10, 19 and 26-week-old SHR and their age-matched control Wistar Kyoto (WKY) rats. Arginase activity as well as expression of arginase I, arginase II, endothelial and inducible NOS were determined in aortic tissue extracts. Levels of L-arginine, NO catabolites and IL-6 (a marker of inflammation) were measured in plasma. Arginase activity/expression was also measured in 10-week-old SHR previously treated with hydralazine (20 mg/kg/day, per os, for 5 weeks). As compared to WKY, SHR exhibited high vascular arginase I and II expression from prehypertensive to established stages of hypertension. However, a mismatch between expression and activity was observed at the prehypertensive stage. Arginase expression was not related either to plasma IL-6 levels or to expression of NOS. Prevention of hypertension by hydralazine significantly blunted arginase upregulation and restored arginase activity. Importantly, arginase activity and blood pressure (BP) correlated in SHR. In conclusion, our results demonstrate that arginase upregulation precedes blood pressure rising and identify elevated blood pressure as a contributing factor of arginase dysregulation in genetic hypertension. They also demonstrated a close relationship between arginase activity and BP, thus making arginase a promising target for antihypertensive therapy.

Animals↗
PubMed2001

Glucocorticoids inhibit lipopolysaccharide-induced up-regulation of arginase in rat alveolar macrophages.

1. As arginase by limiting nitric oxide (NO) synthesis may play a role in airway hyperresponsiveness and glucocorticoids are known to induce the expression of arginase I in hepatic cells, glucocorticoid effects on arginase in alveolar macrophages (AM Phi) were studied. 2. Rat AM Phi were cultured in absence or presence of test substances. Thereafter, nitrite accumulation, arginase activity, and the expression pattern of inducible NO synthase, arginase I and II mRNA (RT - PCR) and proteins (immunoblotting) were determined. 3. Lipopolyssacharides (LPS, 20 h) caused an about 2 fold increase in arginase activity, whereas interferon-gamma (IFN-gamma), like LPS a strong inducer of NO synthesis, had no effect. 4. Dexamethasone decreased arginase activity by about 25% and prevented the LPS-induced increase. Mifepristone (RU-486) as partial glucocorticoid receptor agonist inhibited LPS-induced increase by 45% and antagonized the inhibitory effect of dexamethasone. 5. Two different inhibitors of the NF-kappa B-pathway also prevented LPS-induced increase in arginase activity. 6. Rat AM Phi expressed mRNA and protein of arginase I and II, but arginase I expression was stronger. Arginase I mRNA and protein was not affected by IFN-gamma, but increased by LPS and this effect was prevented by dexamethasone. Both, LPS and IFN-gamma enhanced the levels of arginase II mRNA and protein, effects also inhibited by dexamethasone. As IFN-gamma did not affect total arginase activity, arginase II may represent only a minor fraction of total arginase activity. 7. In rat AM Phi glucocorticoids inhibit LPS-induced up-regulation of arginase activity, an effect which may contribute to the beneficial effects of glucocorticoids in the treatment of inflammatory airway diseases.

Animals↗