CONTEXT: Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of l-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes. OBJECTIVE: To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality. DESIGN: Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months. SETTING: Urban tertiary care center and community clinics in the United States between February 2001 and March 2005. PARTICIPANTS: Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants. MAIN OUTCOME MEASURES: Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality. RESULTS: Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels. CONCLUSIONS: These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.
CONTEXT: Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of l-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes. OBJECTIVE: To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality. DESIGN: Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months. SETTING: Urban tertiary care center and community clinics in the United States between February 2001 and March 2005. PARTICIPANTS: Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants. MAIN OUTCOME MEASURES: Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality. RESULTS: Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels. CONCLUSIONS: These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.
Authors: F T Kaneko; A C Arroliga; R A Dweik; S A Comhair; D Laskowski; R Oppedisano; M J Thomassen; S C Erzurum Journal: Am J Respir Crit Care Med Date: 1998-09 Impact factor: 21.405
Authors: C J Cooper; M J Landzberg; T J Anderson; F Charbonneau; M A Creager; P Ganz; A P Selwyn Journal: Circulation Date: 1996-01-15 Impact factor: 29.690
Authors: P Dias-Da-Motta; V R Arruda; M N Muscará; S T Saad; G De Nucci; F F Costa; A Condino-Neto Journal: Br J Haematol Date: 1996-05 Impact factor: 6.998
Authors: Zhili Shao; Zeneng Wang; Kevin Shrestha; Akanksha Thakur; Allen G Borowski; Wendy Sweet; James D Thomas; Christine S Moravec; Stanley L Hazen; W H Wilson Tang Journal: J Am Coll Cardiol Date: 2012-03-27 Impact factor: 24.094
Authors: Clifford L Cua; Lynette K Rogers; Louis G Chicoine; Molly Augustine; Yi Jin; Patricia L Nash; Leif D Nelin Journal: Eur J Pediatr Date: 2010-12-01 Impact factor: 3.183
Authors: W H Wilson Tang; Kevin Shrestha; Zeneng Wang; Richard W Troughton; Allan L Klein; Stanley L Hazen Journal: J Card Fail Date: 2013-02 Impact factor: 5.712
Authors: Antonella Meloni; Jon Detterich; Alessia Pepe; Paul Harmatz; Tom D Coates; John C Wood Journal: Blood Cells Mol Dis Date: 2014-11-24 Impact factor: 3.039