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

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
L-Arginine, the substrate for nitric oxide (NO) synthesis, is deficient in sickle cell disease (SCD).1-4 Increased NO consumption by cell free plasma hemoglobin5 and reactive oxygen species6,7 leads to decreased NO bioavailability8,9 that is exacerbated by decreased availability of the NO synthase substrate L-arginine. This state of resistance to NO is accompanied by a compensatory up-regulation of NO synthase and non–NO-dependent vasodilators.10-13 Under conditions of low arginine concentration, NO synthase is uncoupled, producing reactive oxygen species in lieu of NO,14,15 potentially further reducing NO bioavailability in SCD and enhancing oxidative stress. Recent reports of elevated arginase activity in SCD16-18 offer another avenue for decreased arginine bioavailability. Arginase, an enzyme that converts L-arginine to ornithine and urea, can limit NO bioavailability through increased consumption of the substrate for NO synthase.19-21 Arginase, which is found predominantly in the liver and kidneys, is also present in human red blood cells22,23 and can be induced in many cell types by a variety of cytokines and inflammatory stimuli.20,24,25 Furthermore, since arginine and ornithine compete for the same transport system for cellular uptake,26,27 a decrease in the ratio of arginine to ornithine resulting from increased arginase activity could further limit arginine bioavailability for NO synthesis.