Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease.
BACKGROUND
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.


METHODS
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.


METHODS
Urban tertiary care center and community clinics in the United States between February 2001 and March 2005.


METHODS
Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants.


METHODS
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.
Department of Emergency Medicine, Children's Hospital and Research Center at Oakland, CA 94609, USA. claudiamorris@comcast.net
Claudia R
CR
Morris
Gregory J
GJ
Kato
Mirjana
M
Poljakovic
Xunde
X
Wang
William C
WC
Blackwelder
Vandana
V
Sachdev
Stanley L
SL
Hazen
Elliott P
EP
Vichinsky
Sidney M
SM
Morris
Mark T
MT
Gladwin
D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000401:mortality; D001119:Arginase / Q000097:blood / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D009952:Ornithine / Q000097:blood; D016016:Proportional Hazards Models
D000596:Amino Acids; D009569:Nitric Oxide; D001120:Arginine; D009952:Ornithine; D001119:Arginase