Altered arginine metabolism in sickle cell disease (SCD). Dietary glutamine and glutamate serve as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Arginine is synthesized endogenously from citrulline primarily via the intestinal-renal axis [80]. Arginase and nitric oxide synthase (NOS) compete for arginine, their common substrate. Asymmetric dimethyl arginine (ADMA) is an arginine analog and NOS inhibitor that is elevated in SCD [59–61]. In SCD, bioavailability of arginine and nitric oxide (NO) is decreased by several mechanisms linked to hemolysis [53, 54, 81, 82]. The release of erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards ornithine production, limiting the amount of substrate available for NO production [53]. The bioavailability of arginine is further diminished by increased ornithine levels because ornithine and arginine compete for the same transporter system for cellular uptake (cationic amino acid transporter—CAT) [83, 84]. Despite an increase in NOS, NO bioavailability is low due to low substrate availability [53], NO scavenging by cell-free hemoglobin released during hemolysis [85], and through reactions with free radicals such as superoxide and other reactive NO species [86–88]. Superoxide is elevated in SCD due to low superoxide dismutase activity [89, 90], high xanthine oxidase activity [87], and potentially as a result of uncoupled NOS [91, 92] in an environment of low arginine and/or tetrahydrobiopterin concentration or insufficient NADPH. Superoxide will react with NO to form reactive nitric oxide species (RNOS) including peroxynitrite [93], which can contribute further to cell damage and cell death. Endothelial dysfunction resulting from NO depletion and increased levels of the downstream products of ornithine metabolism (polyamines and proline) likely contributes to the pathogenesis of lung injury, pulmonary hypertension, and asthma in SCD. This model has implications for all hemolytic processes. This new disease paradigm is now recognized as an important mechanism in the pathophysiology of SCD. Reproduced/modified with permission from the American Society of Hematology [81].
