Arginase Activity In Patients Research Articles

Study of the Arginase Activity and Other Biochemical Parameters in Patients with Coronary Artery Disease in Baghdad Governorate-Iraq

The most prevalent form of heart disease and the main cause of death in both developed and developing nations is CAD. It happens when "plaque," or cholesterol or other fatty deposits that accumulate on the inner wall of the artery, narrows or blocks the arteries that deliver blood to the heart. Over time, chest pain might develop as a result of the reduction in blood flow to the heart caused by this plaque accumulation. The study was designed to find if Arginase acts as a biomarker for diagnosing Coronary Artery Disease (CAD). A total of 90 individual samples were included in the present study, the control group consist of 40 healthy individual samples, while the CAD patients were 50 individual samples. Some biochemical parameters such as fasting blood glucose (FBG), troponin I(TnI), high sensitivity C-reactive protein (hs-CRP), lipid profile, lactate dehydrogenase (LDH), and Arginase activity were analyzed. The results of the current study showed no significant differences in the average age of patients (67.00±6.78) when compared with the control group (61.10±6.46), P>0.05. A significant increase Was found in the FBI level, cholesterol, triglycerides, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), TnI, hs-CRP, LDH, and Arginase activity in the patient's group when compared with the control group. While significant decrease (P<0.05) was revealed in the high-density lipoprotein (HDL) level in CAD patients in comparison to the control group. Also, there was a positive significant correlation between Arginase activity with each age and FBG. As for the ROC operator curve for Arginase, it was found that the area under the curve (AUC) was 0.953 with a sensitivity of 90%, and specificity of 95%. The results in the present study indicate a possible use of Arginase as a diagnostic marker for CAD.

The level of nitric oxide and arginase activity in patients with arterial hypertension and diabetes mellitus during COVID-19

The aim of this study was to assess the level of nitric oxide production and arginase activity in patients with arterial hypertension and type II diabetes mellitus during infection with SARS-CoV-2. The study groups included patients with arterial hypertension, patients with arterial hypertension combined with a severe course of COVID-19 and patients who, in addition to arterial hypertension and COVID-19, were suffering from type II diabetes mellitus. The volunteers without any clinical signs of diseases and normal blood pressure formed the control group. It has been established that arterial hypertension, combined with COVID-19 occurs along with reduced L-arginine, nitric oxide, superoxide dismutase activity and increased arginase activity. At the same time, the presence of arterial hypertension in patients with diabetes and coronavirus disease is accompanied by a decline in the content of L-arginine and arginase activity. Our study’s results may help scientists find new pharmacological targets in the future treatment of coronavirus disease and comorbid disorders. Keywords: arginase, COVID-19, diabetes mellitus, hypertension, L-arginine, nitric oxide, superoxide dismutase

Modulating effect of HERV-W ENV on peripheral blood monocytes in patients with different types of multiple sclerosis

The aim of the study was to determine the effect of the HERV-W ENV glycoprotein on the functional and metabolic characteristics of intact and stimulated peripheral blood monocytes, depending on the type of multiple sclerosis (MS), which can contribute to our understanding of their pathogenetic role in the development of neurological disorders and to design of novel therapeutic agents. Materials and methods. To determine the reserve capacity index (Rci) of cytokine production, HERV-W ENV glycoprotein, E. coli lipopolysaccharide (LPS) or ssRNA40/LyoVec were added to the monocyte-enriched cell suspension as agonists of TLR4 and TLR7/8. The study also included the evaluation of arginase activity in cell lysates of the monocyte fraction. The study involved 37 patients with relapsing-remitting type and 19 patients with progressive type of MS. The control group included 32 healthy individuals. Results. In patients with MS of both groups, the reserve capacity of monocytes to produce IL-1β was lower than in healthy individuals, while the reserve capacity to produce TNF-α and IL-10 was almost twice as high as in the control group. This index for IL-1RA in monocytes obtained from the group with progressive MS and stimulated with HERV-W ENV was 2 times lower than the control; thus increased IL-1β values provoke chronic inflammation. The highest arginase activity in patients with relapsing-remitting MS was observed when monocytes were cultured with HERV-W ENV and LPS. In patients with progressive MS, during the cultivation of monocytes with LPS, arginase activity was significantly reduced relative to the control. Conclusions. The results obtained indicate functional and metabolic changes in peripheral blood monocytes upon stimulation with TLR4 and TLR7/8, which may be associated with the disease course. In progressive MS, stimulation with HERV-W ENV leads to an imbalance of pro-inflammatory and regulatory cytokines, contributing to a chronic inflammation and, as a consequence, to a more severe course of the disease.

STUDY THE LEVEL OF ARGINASE ACTIVITY AND ITS CORRELATION WITH LIVER AND KIDNEY FUNCTIONS FOR PATIENTS WITH TYPE-2 DIABETES IN NINEVEH GOVERNORATE

Background: Arginase plays an essential role in type 2 diabetes. Aim of the study: The study aimed to determine the level of arginase activity in individuals patients with diabetes mellitus type 2 (DMT2) and study the correlation between arginase activity and the investigated variables. Patients and material methods: The study included 201 adults divided into two groups: those with type II diabetes (136 people) and healthy (65 people). Blood non-fasting persons had their arginase activity, glucose, glycated haemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine levels tested.Results: The findings showed that the level of arginase activity in patients with type 2 diabetes was significantly increased (p≤0.0001) in comparison with those with a healthy adult, but there was no significant differentiation in the level of activity in arginase for each of the factors of sex and age. A positive significant correlation (P=0.01) was found between Glucose (r=0.584), HbA1c (r=0.454), AST(GOT) (r=0.433), ALT (GPT) (r=0.295), ALP (r=0.639), Urea (r=0.667), and Creatinine (r=0.658). Conclusion: In patients with diabetes mellitus type 2, arginase activity plays a critical role. In addition, people with type 2 diabetes have an increased level of arginase activity, which directly impacts their liver and kidney functioning.

L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.

Functional and metabolic characteristics of peripheral blood mononuclear phagocytes in patients with different clinical courses of multiple sclerosis

Functional and metabolic features of intact and stimulated mononuclear phagocytes were studied in patients with different clinical courses of multiple sclerosis, the study included 66 patients with relapsing-remitting and 32 patients with progressive course of multiple sclerosis. The state of the mononuclear phagocytes was characterized by expression of costimulatory molecules and direction of L-arginine metabolism. Relative quantities of CD80, CD86 and PD-L1 positive monocytes were determined with Phycoerytrin-labeled monoclonal antibodies in immunofluorescence test in peripheral blood and after culture in parallel series with addition of: (a) E.coli lipopolysaccharide (a stimulator of TLR4), (b) a single-stranded RNA – preparation ssRNA40/LyoVec (a stimulator of TLR7/8), (c) IL-4 (an anti-inflammatory interleukin). The formation of NO was determined by the amount of nitrite in the culture supernatants, arginase activity was determined in cell lysates of the monocyte fraction. We showed that functional and phenotypic characteristics of monocytes depend on the clinical course of multiple sclerosis. In patients with progressive course, the relative number of CD86+ cells was significantly higher and PD-L1+ cells significantly lower than in patients with relapsing-remitting course and healthy persons, in patients with relapsing-remitting course the number of PD-L1+ cells was increased. The number of CD80+ cells did not show any significant difference in the investigated groups of patients relative to the control group. In vitro stimulation of peripheral blood monocytes with TLR4/8 produced a significant increase in the number of CD86+ and decrease in the number of PD-L1+ cells in patients with the progressive course. In patients with the relapsing-remitting course LPS produced an increase in number of PD-L1+ cells. We did not find any difference in activity of the arginase pathway of L-arginine metabolism in the intact monocyte fraction of peripheral blood in patients with multiple sclerosis versus the control group, but stimulation with TLR4 agonist of mononuclear cells of patients with progressive course caused significant increased arginase activity versus baseline. At the same time, versus control cells arginase activity in patients with the progressive course decreased after LPS treatment, but trended to increase after TLR7/8 treatment. In patients with the relapsing-remitting course these changes had a similar direction but were less expressed. The results may be considered as an indication of the activation of peripheral blood monocytes and their polarization trend in the M1 direction in patients with the progressive course of multiple sclerosis, these changes could be considered as signs of violation of autoimmune regulatory mechanisms in multiple sclerosis.

The role of arginase and ornithine decarboxylase activity changes in the pathogenesis of liver injury in patients with acute leukemia with concomitant obesity

Objective – to investigate the role of arginase, ornithine decarboxylase (ODC) activity in the liver injury pathogenesis in patients with acute myeloid (AML) and acute lymphoblastic (ALL) leukemia with concomitant obesity.Materials and methods. We examined 40 patients with newly diagnosed acute leukemia, including 20 patients with AML (10 (50%) men / 10 (50%) women) and 20 patients with ALL (12 (60%) men / 8 (40%) women), aged 16-77 years. The indicators of complete and biochemical blood tests were analyzed. Arginase and ODC activity was measured in the blood serum.Study results. Liver injury in patients with AML and ALL was characterized by cytolytic and cholestatic syndromes development. Arginase activity in patients with AML 3.9-fold, and in patients with ALL – 1.8-fold exceeded normal ranges (p<0.05). ODC activity in patients with AML and ALL was 1.9-fold higher compared to normal values (р<0.05).Conclusions. Manifestation of AML and ALL is accompanied by increased activity of arginase and ODC, which is associated with biochemical liver tests violation.

The arginase pathway of L-arginine metabolism of peripheral blood lymphocytes in patients with acne vulgaris

The mechanisms of development of the inflammatory process of the pilosebaceous apparatus in patients with acnе vulgaris are not fully understood, and variations in bacterial colonization are one of the key elements of the inflammatory process. Under the pathological conditions caused by pus-forming cocci which induce the production of proinflammatory cytokines, there is an increase in arginase expression. The capacity for film formation in selected strains was determined by the cultural properties (increased viscosity of the colony biomass) and by differential interference contrast microscopy using a dark field condenser and fluorescence microscopy. Arginase activity (μmole urea/min•mg of protein) was determined spectrophotometrically at 520 nm on saponin-perimabilized lymphocytes of peripheral blood by the rate of urea formation. The cultures of film-forming and planktonic forms of Staphylococcus epidermidis and Staphylococcus aureus were isolated from purulent pustules of 44 patients, aged 18–30. 63.6% of clinical strains of film-forming staphylococci were isolated, out of which 15 strains (53.6%) were S. aureus and 13 strains (46.4%) S. epidermidias. It was found that the arginase activity in patients (film-forming S. aureus) was significantly higher than in practically healthy donors (control) and was equal to 0.262 ± 0.006 and 0.279 ± 0.005 (planktonic form of S. aureus) versus 0.087 ± 0.009 μmole urea / min∙mg of protein in the control. The arginase activity in patients (film-forming S. epidermidis) was significantly higher than in practically healthy donors and was equal to 0.281 ± 0.009 and 0.297 ± 0.006 (planktonic form of S. epidermidis) versus 0.087 ± 0.009 μmol urea / min∙mg of protein in the control. After the auto-vaccine therapy and the administration of the probiotic Lacidofil (Institut Rosell Inc., Canada), enzyme activity decreased significantly in both experiments, however it had not attained control levels. The enzyme activity decreased through the administration of a vaccine, which in turn has an immunomodulating and immunostimulating effect. In addition, comparing the data of the arginase activity after treatment in patients with S. epidermidis, there was a slight decrease in the enzyme activity. This result is probably due to the formed tolerance of the immune system to commensal microorganisms. It was found that all patients had a moderate dysbiosis, which was accompanied by a deficiency of the main normal symbionts of the intestine. After treatment, all patients experienced significant improvementst in the microbiocenosis of the intestine in the direction of normalization of parameters and improvement of the skin condition. Increase in arginase activity in patients with acne vulgaris indicates the competition of this enzyme with NO-synthases for the substrate L-arginine and the alteration of physiological reactions in the organism caused by staphylococci which induce the phagocytic response and the cytokines production of the humoral system.

Arginase Inhibition Suppresses Breast Cancer Cell Proliferation

Breast cancer is the second most common cause of cancer worldwide. It is recognized to be the most common cancer in women. It is also considered as the second leading cause of cancer death in women in the United States. There is accumulating evidence of increased arginase activity in patients with breast cancer. Arginase, an enzyme of the urea cycle, catalyzes the hydrolysis of L‐arginine to urea and L‐ornithine. L‐ornithine is converted to polyamines by the enzyme ornithine decarboxylase (ODC). Polyamines such as spermidine and spermine have an important role in cell proliferation. Hence, polyamines are also found to have an important role in tumor development and growth. Levels of polyamines are found to be 2–3 times higher in breast cancer cells than in normal surrounding tissue.We studied the effects of arginase inhibition on breast cancer cells and endothelial cells in vitro. Our experiments utilized MCF‐7 breast cancer cells or bovine aortic endothelial cells. Arginase activity was measured in cells treated with or without the novel arginase inhibitor; 2(S)‐amino‐6‐boronohexanoic acid (ABH). Additionally, the effect of ABH treatment on cells proliferation in vitro was determined using cell proliferation assay.Our results show that arginase inhibition caused a concentration dependent suppression of MCF‐7 cell proliferation with a maximum inhibitory concentration of 500 μM. This dose of ABH resulted in a 30% decrease in cell proliferation versus untreated controls. Arginase activity was measured in cells treated with ABH and was decreased by 60% versus controls. Interestingly, while ABH inhibited arginase activity in endothelial cells, it did not have any effect on the proliferation rate of endothelial cells. Our results indicate that arginase can be considered a new therapeutic target for suppressing breast cancer cell growth. Arginase inhibitors represent a potential cancer therapy in tumors with elevated arginase activity.Support or Funding InformationThe University of Jordan Deanship of Research

Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction.

Endothelial dysfunction contributes to the development of vascular complication in diabetes. Arginase has emerged as a key mechanism behind endothelial dysfunction by its reciprocal regulation of nitric oxide production by substrate competition. We hypothesized that increased arginase activity in patients with type 2 diabetes shifts the metabolism of l-arginine from nitric oxide synthase to arginase resulting in an increase in the plasma ratio of ornithine/citrulline, and that this ratio is associated with endothelial dysfunction. Forearm endothelium-dependent vasodilatation and endothelium-independent vasodilatation were determined in 15 patients with type 2 diabetes and 10 healthy controls and related to amino acids reflecting arginase and nitric oxide synthase activity. Compared to healthy controls, patients with diabetes had impaired endothelium-dependent vasodilatation and endothelium-independent vasodilatation. The ratios of ornithine/citrulline and proline/citrulline were 60% and 95% higher, respectively, in patients with diabetes than in controls (p < 0.001). The plasma ornithine/arginine ratio was 36% higher in patients with diabetes, indicating increased arginase activity. These ratios were inversely correlated to endothelium-dependent vasodilatation and endothelium-independent vasodilatation. Patients with diabetes and macrovascular complications have increased amino acid ratios reflecting a shift in arginine metabolism due to arginase activation. These changes are inversely related to endothelial function supporting that arginase activity contributes to endothelial dysfunction.

Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis

BackgroundSerum arginase levels have been shown to be elevated in conditions, such as trauma, cancer, chronic wounds, pregnancy, and diabetes. This also has been found to be true in atopic diseases, such as asthma and allergic rhinitis. ObjectiveTo study arginase activity in patients with atopic dermatitis (AD). MethodsIn this pilot study, arginase activity levels in 15 pediatric patients with AD were compared with those in controls to determine whether arginase levels in AD are altered as in patients with other atopic diseases. ResultsIn contrast to the other diseases studied, arginase activity was found to be decreased in granulocytes and in the plasma of patients with AD compared with controls. This finding was coupled with a trend toward higher L-arginine plasma levels. ConclusionIn AD, a different mechanism of arginine metabolism seems to be stimulated, leading to the formation of nitric oxide pathway components causing suppression of the arginase pathway and impairment in skin hydration, collagen synthesis, and wound healing.

Arginase Activity in Patients with Breast Cancer: An Analysis of Plasma, Tumors, and Its Relationship with the Presence of the Estrogen Receptor

Background: Breast cancer is an important cause of cancerrelated death in women. In this pathological condition, arginase plays a role by providing ornithine as a substrate for the biosynthesis of polyamines which are important in tumor progression. The aim of this work was to determine the arginase activity in the plasma and tumors of patients with breast cancer; also, we investigated the relationship between this activity and the presence of the estrogen receptor. Patients and Methods: We evaluated the plasma arginase activity levels in 80 women with breast cancer and 42 healthy control subjects. We also measured the arginase levels in 42 breast cancer biopsies and 42 control tissues. Results: The mean activity of arginase in plasma was higher in breast cancer patients (0.78 nM/min/mg protein ± 0.04; p = 0.001) than in healthy volunteers (0.53 nM/ min/mg protein ± 0.04); however, this difference was indicative of patients in the advanced stages of the disease (n = 38, stage III; p < 0.0001). In addition, we did not find a relationship between the estrogen receptor and arginase activity. Conclusion: Our results show a higher arginase activity in the plasma of patients in the advanced stages of the disease, suggesting that arginase activity could serve as a possible biological marker of breast cancer progression.

Arginase activity in carcinoma of the gallbladder: a pilot study

Carcinoma of the gallbladder is the third most common cancer of the gastrointestinal tract. Recent studies have shown increased arginase activity in various malignancies. The main aim of this study was to evaluate whether arginase activity increases in carcinoma of the gallbladder. The arginase activity was evaluated in serum and gallbladder tissue in 22 patients with histologically proven carcinoma of the gallbladder and 20 patients with cholecystitis using spectrophotometry and western blot assay. The Student's t-test, analysis of variance, and Student-Newman-Keuls test were used for comparison of data and for statistical significance. The mean tissue arginase and serum arginase activity (118.64+/-17.45 and 15.91+/-1.91, respectively) in cases of carcinoma of the gallbladder were significantly higher in comparison with cholecystitis (86.37+/-4.45 and 12.73+/-0.72, respectively). Subgroup analysis showed stage III gallbladder carcinoma had the maximum tissue arginase activity (142.00+/-21.68 U/g of tissue) followed by stage II (124.15+/-19.88) and stage I (108.46+/-6.73). This significant rise in mean tissue arginase and serum arginase activity in patients with gallbladder cancer probably supports an association between arginase activity and the malignancy.

Smoking increases salivary arginase activity in patients with dental implants

It is believed that an increased arginase activity may lead to less nitric oxide production, which consequently increases the susceptibility to bacterial infection. Considering the hypothesis that smoking may alter the arginase activity and that smoking is considered a risk factor to dental implant survival, the present study aimed at evaluating the effect of smoking on the salivary arginase activity of patients with dental implants. Salivary samples of 41 subjects were collected: ten non-smoking and with no dental implants (group A), ten non-smoking subjects with dental implants (group B), ten smoking subjects with implants (group C), and 11 smoking subjects with no dental implants (group D). The levels of salivary arginase activity were determined by the measurement of L-ornithine and expressed as mIU/mg of protein. A significant increase in the salivary arginase activity was verified in groups C (64.26 +/- 16.95) and D (49.55 +/- 10.01) compared to groups A (10.04 +/- 1.95, p = 0.00001 and p = 0.0110, groups C and D, respectively) and B (11.77 +/- 1.45, p = 0.00001 and p = 0.0147, groups C and D, respectively). No significant difference was found between groups C and D (p = 0.32). Within the limits of the present study, it can be concluded that salivary arginase activity is increased in smoking subjects with dental implants in contrast to non-smoking subjects with dental implants, therefore suggesting a possible mechanism by which cigarette smoking may lead to implant failure. The analysis of salivary arginase activity may represent an important tool to prevent implant failure in the near future.

Effectiveness of scaling and root planing versus modified Widman flap on nitric oxide synthase and arginase activity in patients with chronic periodontitis

Nitric oxide (NO) is synthesized from the conversion of L-arginine to L-citrulline by NO synthase (NOS). Arginase, which is an arginine-depleting enzyme, can compete with NOS for the common substrate L-arginine and thus inhibit NO production. In the present study, we aimed to examine the correlation between the arginase and NOS activity in patients with chronic periodontitis and to compare the effects of scaling and root planing and modified Widman flap procedures on enzyme activity. The study included 13 patients diagnosed with chronic periodontitis. Using a split-mouth design, the defects showing>or=7 mm of attachment loss were treated either with scaling and root planing or with modified Widman flap. Gingival biopsies from both sites were obtained at baseline and 2 months after periodontal treatment. Immunohistochemical staining was performed for evaluating NOS expression and specific arginase activity was determined spectrophotometrically. Although inflamed periodontal tissues demonstrated a strong inducible NOS (iNOS) expression at baseline, immunostaining decreased after periodontal treatment. iNOS expression intensity and the number of inflammatory cells showing iNOS expression were found to be higher in the scaling and root planing group compared to the modified Widman flap group. The specific activity of arginase was measured as 0.18+/-0.07 IU/mg protein in the modified Widman flap group and 0.25+/-0.11 IU/mg protein in the scaling and root planing group at baseline. After periodontal therapy, the enzyme level was increased to 0.68+/-0.14 IU/mg protein in the modified Widman flap and to 1.10+/-0.23 IU/mg protein in the scaling and root planing group. This study was the first report of evaluating the involvement of the arginine-NO pathway in chronic periodontitis and this might be considered to be of value in understanding the periodontal disease mechanisms.

The Arginine-to-Ornithine Ratio: Biomarker of Arginase Activity and Predictor of Mortality in Sickle Cell Disease.

Sickle cell disease (SCD) is characterized by a state of nitric oxide resistance and limited bioavailability of L-arginine, the substrate for nitric oxide synthesis. While nitric oxide resistance occurs secondary to inactivation of nitric oxide by plasma hemoglobin released during intravascular hemolysis and by reactive oxygen species, mechanisms that limit L-arginine are not known. We hypothesized that increased arginase activity in patients with SCD would shift arginine metabolism away from nitric oxide production and towards ornithine metabolism, contributing to endothelial dysfunction and the development of pulmonary hypertension. Furthermore, since arginine and ornithine compete for the same transport system for cellular uptake, a decrease in the Arginine-to-Ornithine ratio resulting from increased arginase activity could also impair arginine bioavailability for nitric oxide production. Our goal was to evaluate associations between plasma arginase, arginine metabolism and pulmonary hypertension and prospective mortality in SCD. Plasma and erythrocyte arginase activity and amino acid levels were determined for patients with SCD and compared to ethnically matched control subjects. A diagnosis of pulmonary hypertension by Doppler-echocardiogram and prospective mortality were determined over 30 months of sequential patient enrollment. Plasma arginase activity was significantly elevated in patients with SCD compared to controls (2.2±2, n=140 vs. 0.4±2 μmol/ml/hr, n=45, p=0.007), trending higher in subjects with pulmonary hypertension. Plasma arginase activity correlated with the Arginine-to-Ornithine ratio (r=−0.33, p=0.0004), and lower ratios were associated with greater severity of pulmonary hypertension (1.1±0.4 vs. 0.8±0.4 vs. 0.6±0.3, controls vs. SCD without pulmonary hypertension vs. SCD with pulmonary hypertension, respectively, p=0.01) and independently associated with mortality (0.7±0.4 vs. 0.5±0.2, alive vs. dead, p=0.003; Risk Ratio = 4.9 [CI: 1.4, 17.1], p=0.002, for a low Arginine-to-Ornithine ratio; 13 deaths total). The mortality risk ratio increased to 7.0 ([CI: 1.6, 31.6], p=0.01), when the Arginine-to-Ornithine ratio was adjusted for creatinine, likely reflecting the impact of renal disease. Plasma arginase activity correlated with markers of increased hemolytic rate, including LDH (r=0.44, p<0.001), AST (r=0.39, p<0.002), reticulocyte count (r=0.25, p<0.001), and Hct (r= −0.25, p<0.001), and was higher in erythrocytes of SCD patients compared to controls (37.7±2.9, n=16 vs 23.5±1.7 nmol/mg/min, n=45, p<0.0001), consistent with hemolytic release of erythrocyte arginase. These data support a novel mechanism of disease whereby hemolysis not only liberates vasoactive hemoglobin but also releases erythrocyte arginase, which contributes to impaired nitric oxide bioavailability, endothelial dysfunction, pulmonary hypertension and death. The Arginine-to-Ornithine ratio, a reflection of arginase activity, may represent a useful biomarker of disease severity and risk of death in patients with SCD.

Arginase, a new marker of mammary carcinoma

Activities of arginase, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were determined in sera obtained in a group of healthy women, women with verified carcinoma of the breast, benign mastopathy, a group of patients with carcinoma of various organs and a group of patients with acute viral hepatitis. Preoperative values of serum arginase activity in patients with breast carcinoma were up to 4-fold those found in healthy women. Sensitivity of the test was 86%. After the surgery, the activity decreased abruptly during the first week and normalised within 15–30 days. In benign diseases of the breast, the activity of arginase was normal. Serum arginase activity is raised in both benign and malignant liver diseases, however, the quotients alanine aminotransferase/arginase, aspartate aminotransferase/arginase and alkaline phosphatase/arginase differ significantly. Thus, use of alanine aminotransferase/arginase quotient implies a high degree of confidence in differentiating between increased arginase activity in mammary carcinoma (alanine aminotransferase/arginase = 0.572 ± 0.278) and high arginase activity in hepatitis (alanine aminotransferase/arginase = 12.226 ± 1.822).

Crystallization of arginase from normal and cirrhotic human liver.

IT has been demonstrated that patients with liver disorders are particularly susceptible to ammonia intoxication1. Since ammonia is detoxified by urea synthesis, study of the enzymes of the Krebs–Hensleit cycle in the normal and abnormal liver might provide useful information. Decrease of liver arginase activity in patients suffering from cirrhosis and hepatic coma has been reported by Ugarte, Pino and Valenzuela2. In our study, arginase was crystallized from a ‘normal’ human and a cirrhotic human liver and the catalytic efficiency of the enzymes from the two sources was compared.