Hemolysis-Associated Pulmonary Hypertension in Sickle Cell Disease: Global Disruption of the Arginine-Nitric Oxide Pathway
Claudia R. Morris.
Nitric oxide is inactivated in sickle cell disease (SCD), while bioavailability of L-arginine, the substrate for nitric oxide synthesis is diminished. Impaired nitric oxide bioavailability represents the central feature of endothelial dysfunction, and is a major factor in the pathophysiology of SCD. Inactivation of nitric oxide correlates with hemolytic rate and is associated with erythrocyte release of cell-free hemoglobin and arginase during intravascular hemolysis. Accelerated consumption of nitric oxide is enhanced further by the inflammatory environment of oxidative stress that exists in SCD. Based upon its critical role in mediating vasodilation and inhibiting cell growth, decreased nitric oxide reactivity has also been implicated in the pathogenesis of pulmonary hypertension (PHT). Secondary PHT, a common life-threatening complication of SCD, also occurs in thalassemia and most hereditary and chronic hemolytic disorders. Aberrant arginine metabolism contributes to endothelial dysfunction and PHT in SCD, and is therefore 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 artery hypertension. Decompartmentalization of hemoglobin into plasma consumes endothelial nitric oxide and thus drives a metabolic requirement for arginine, whose bioavailability is further limited by arginase activity. New treatments aimed at maximizing both arginine and nitric oxide bioavailability through arginase inhibition, suppression of hemolytic rate, or oral arginine supplementation may represent novel therapeutic strategies for this common pulmonary complication of hemolytic disorders.
Keywords: Pulmonary hypertension, sickle cell disease, arginine, nitric oxide, arginase, hemolysis
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