Sickle cell disease is characterized by a state of nitric oxide (NO) resistance and limited bioavailability of L-arginine, the substrate for NO synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension and patient outcome.
To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension and prospective mortality.
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 for survival up to 49 months.
Urban, tertiary care center and community clinics.
Two hundred twenty-eight patients with sickle cell disease aged 18 to 74 years and 36 control subjects.
Main Outcome Measures
Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality.
Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in subjects with secondary pulmonary hypertension. Arginase activity correlated with the arginine-to-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 [1.2, 5.2], p=0.006). Global arginine bioavailability, characterized by the arginine-to-(ornithine plus citrulline) ratio, was also strongly associated with mortality (risk ratio: 3.6; [1.5, 8.3], p<0.001). Increased plasma arginase activity was highly correlated with increased intravascular hemolytic rate and, to a lesser extent, markers of inflammation and soluble adhesion molecule levels.
These data support a novel mechanism of disease in which hemolysis contributes to reduced NO bioavailability and endothelial dysfunction, via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges NO. The arginine-to-ornithine and arginine-to-(ornithine plus citrulline) ratios are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.