Abstract
Endothelial Nitric Oxide Synthase (eNOS) produces nitric oxide (NO) within the endothelial cell layer of blood vessels. NO is a potent vasodilator and perturbations of NO signaling have been associated with cardiovascular diseases such as diabetes, atherosclerosis and hypertension. L‐arginine is a semi‐essential amino acid that is the substrate for eNOS. However, L‐arginine is also the substrate for the arginases, enzymes that metabolize L‐arginine into ornithine and urea. The potential for arginases to compete with eNOS for arginine has been investigated as an underlying reason for endothelial dysfunction and a mechanism to account for the arginine paradox. Previously we showed that the activity of eNOS constructs targeted to different intracellular locations was equally inhibited by Arginases I and II, despite their different locations within the subcellular environment. These results argue against the concept that spatially restricted pools of L‐arginine account for the arginine paradox. Furthermore, the addition of excess extracellular L‐arginine failed to override the inhibitory effect of arginase I which suggests a more complex mode of eNOS inhibition. Therefore the current study was designed to investigate the involvement of other mechanisms by which arginases inhibit eNOS and included cell free activity assays, inhibition of arginases, eNOS monomer/dimer ratios and superoxide production.
Published Version
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