Arginase activity in erythrocytes of healthy and ill children

Azizi, E; Dror, Yosef; Wallis, Kathleen

doi:10.1016/0009-8981(70)90063-x

Cited by 42 publications

(33 citation statements)

References 9 publications

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“…Arginase is an essential enzyme in the urea cycle, responsible for the conversion of arginine to ornithine and urea [124]. Found predominantly in liver and kidneys [125], arginase is also found in the red blood cells of humans and other primates [126, 127], making it an intriguing enzyme to study in hemolytic disorders. Plasma arginase activity is elevated in SCD as a consequence of inflammation, liver dysfunction and, most significantly, by the release of erythrocyte arginase during intravascular hemolysis, which has been demonstrated by the strong correlation between plasma arginase leves and cell-free hemoglobin levels and other markers of increased hemolytic rate “Fig (2)” [22].…”

Section: Novel Role Of Arginase In Pulmonary Diseasementioning

confidence: 99%

Nitric Oxide and Arginine Dysregulation: A Novel Pathway to Pulmonary Hypertension in Hemolytic Disorders

Morris¹,

Gladwin²,

Kato³

2008

CMM

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Secondary pulmonary hypertension (PH) is emerging as one of the leading causes of mortality and morbidity in patients with hemolytic anemias such as sickle cell disease (SCD) and thalassemia. Impaired nitric oxide (NO) bioavailability represents the central feature of endothelial dysfunction, and is a major factor in the pathophysiology of PH. Inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate arginine during the process of intravascular hemolysis. Rapid consumption of NO is accelerated by oxygen radicals that exists in both SCD and thalassemia. A dysregulation of arginine metabolism contributes to endothelial dysfunction and PH in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and pulmonary arterial hypertension. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, or use of NO donors represent potential therapeutic strategies for this common pulmonary complication of hemolytic disorders.

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Section: Novel Role Of Arginase In Pulmonary Diseasementioning

confidence: 99%

Nitric Oxide and Arginine Dysregulation: A Novel Pathway to Pulmonary Hypertension in Hemolytic Disorders

Morris¹,

Gladwin²,

Kato³

2008

CMM

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“…This effect may be beneficial in patients with sickle cell disease and/ or other haemolytic disorders, characterised by a state of relative NO deficiency. In sickle cell disease (and possibly in other haemolytic disorders), a haemolysis-associated endothelial dysfunction is caused by the release of erythrocyte haemoglobin, which scavenges NO (Reiter et al, 2002), and of erythrocyte arginase, which metabolises l-arginine, the substrate for NO synthesis (Belfiore, 1964;Azizi et al, 1970;Morris et al, 2003;Schnog et al, 2004;Morris et al, 2005) as well as a possible impairment of the pulmonary vasodilatory effects of NO (Voelkel et al, 1995(Voelkel et al, , 1999.…”

mentioning

confidence: 99%

Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension

et al. 2005

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SummaryPulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at‐risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure [50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0·3–17, P = 0·043] and increased the 6‐min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI: 40–117, P = 0·0012). Transient headaches occurred in two patients and transient eye‐lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6‐min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

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“…29 In addition to hemoglobin decompartmentalization and NO scavenging, 30 hemolysis also releases erythrocyte arginase, an enzyme that converts L-arginine, the substrate for NO synthesis, to ornithine, thereby further reducing the systemic availability of NO. [31][32][33][34] NO is a regulator of smooth muscle tone and platelet activation, and reductions in nitric oxide plasma levels lead to smooth muscle dystonias, including hypertension, gastrointestinal contractions, and erectile dysfunction, as well as clot formation. [35][36][37][38] The best protection against NO depletion and thereby these consequences would be to stop hemolysis.…”

Section: Introductionmentioning

confidence: 99%

Eculizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Hill

2009

Clinical Medicine. Therapeutics

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Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired clonal stem cell disorder resulting in hemolysis and thrombosis. A somatic mutation in the phosphatidylinositol glycan A gene in hematopoietic stem cells results in a deficiency of the complement regulatory proteins, CD55 and CD59. There is a consequent increased sensitivity to complement mediated lysis. Eculizumab is a recombinant, humanized monoclonal antibody directed against C5 of the complement system. It blocks terminal complement activation and the formation of the membrane attack complex. It has been demonstrated in 3 clinical studies that this blockade of the terminal complement system effectively and significantly prevents intravascular hemolysis thereby abolishing or reducing the need for transfusions, reduces thromboses, improves quality of life and appears to prevent renal damage and improve pulmonary pressures. The drug is very well tolerated with few safety concerns. Case reports of the use of eculizumab in pregnancy, cold agglutinin disease and atypical hemolytic syndrome are also described.

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Arginase activity in erythrocytes of healthy and ill children

Cited by 42 publications

References 9 publications

Nitric Oxide and Arginine Dysregulation: A Novel Pathway to Pulmonary Hypertension in Hemolytic Disorders

Nitric Oxide and Arginine Dysregulation: A Novel Pathway to Pulmonary Hypertension in Hemolytic Disorders

Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension

Eculizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria

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