Dysregulated Arginine Metabolism, Hemolysis-Associated Pulmonary Hypertension and Mortality in Sickle Cell Disease

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 07/2005; 294(1):81-90. DOI: 10.1001/jama.294.1.81
Source: PubMed


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.
To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and 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 up for survival up to 49 months.
Urban tertiary care center and community clinics in the United States between February 2001 and March 2005.
Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants.
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 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.
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.

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    • "Both isoforms, however, have been found in vascular tissue (Bachetti et al., 2004; Berkowitz et al., 2003). Elevated arginase activity has been associated with cardiovascular pathologies such as hypertension, diabetes, atherosclerosis, ischemic reperfusion injury, erectile dysfunction and sickle cell anemia (Bagnost et al., 2008; Bivalacqua et al., 2007; Jeyabalan et al., 2008; Morris et al., 2005; Romero et al., 2008). In these conditions, elevation of arginase has been shown to mediate vascular dysfunction through limiting nitric oxide (NO) production or availability. "
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    • "NO metabolism is very important in sickle cell disease. We, and others have shown that it is dysregulated [17], [44], and the measurement of exhaled NO has been used in clinical studies in sickle cell disease [24]. Both decreased hematocrit and increased free plasma hemoglobin have been described to contribute to the vaso-occlusive events found in SCD, leading to painful episodes and possible organ damage [44], [45]. "
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    • "We simultaneously measured Arg, ADMA, SDMA, MMA, Cit, and Orn by liquid chromatography-tandem mass spectrometry (LC-MS/MS) [39]. The ratio Arg/(Orn + Cit), as index of global Arg availability [40] [41], and the ratio Orn/Cit, as indicator of the relative activity of arginase and NOS [19], were computed. All the determinations were performed both in plasma and in lysed RBCs. "
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