Uncoupling of NOS

Recent studies indicate that in addition to NAD(P)H oxidase, nitric oxide synthase can produce »O2- in conditions of substrate (arginine) or cofactor (tetrahydrobiopterin) (BH4) deficiency.32,40 These findings have led to the concept of "NOS uncoupling", where the activity of the enzyme for NO production is decreased in association with an increase in NOS-dependent *O2- formation. All NOS isoforms require BH4 for NOS homodimerization and electron transfer during arginine oxidation.72 BH4 influences NOS through multiple mechanisms. It has the ability to shift the heme iron to its high spin state, it promotes arginine binding, and it stabilizes the active dimeric form of the enzyme as well as stabilizes the ferrous heme iron coordination structure.72 Whereas the structural effects of BH4 are mimicked by pterin analogues independent of their oxidation state, pterins must be in the tetrahydro state in order to support NO synthesis, suggesting a redox role of BH4. Thus decreased bioavailability of BH4 or oxidation of BH4 to produce cofactor-inactive pterins, mainly dihydropterin and dihydrobiopterin, results in BH4-deficient NOS that catalyzes formation of *O2- and H2O2.40,41 In the uncoupled state, vascular »O2-production appears to be partially mediated by BH4-dependent eNOS uncoupling in various vascular pathologies, including atherosclerosis,73 diabetes,74 hyperhomo-cysteinemia,75 and hypertension.41,76,77 In experimental models of hypertension, it has been shown that hypertension is associated with increased NAD(P)H oxidase-derived *O2-, leading to increased ROS bioavailability, which causes oxidation of

BH4 and consequent uncoupling of eNOS, which further contributes to ROS production.41 The potential role of uncoupling of NOS as a source of ROS in hypertension is further supported in human studies where increased endothelial •O2- production in vessels from diabetic and hypertensive patients is inhibited by sepiapterin, precursor of BH4 78,79 The relative importance of NOS- vs. NAD(P)H oxidase-mediated *O2- generation in hypertension probably relates, in part, to the magnitude of endothelial dysfunction, since most conditions in which *O2- is derived from NOS are associated with marked endothelial dysfunction.32

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