Molecular Mechanisms of Endothelial NO Synthase Uncoupling

Abstract

Nitric oxide (NO) is a gaseous signaling molecule and effector in various biological processes. In mammalian cells, NO is produced by a family of NO synthases (NOS). Three NOS isoforms have been identified as: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). In addition to NO, NOS also produces superoxide anion. This phenomenon is named NOS uncoupling as superoxide generation mainly occurs when NOS is not coupled with its cofactor or substrate. nNOS was first found to produce superoxide under L-arginine depletion condition. Further studies demonstrated that superoxide production is a general feature of all three NOS isoforms. In particular, superoxide generated from uncoupled eNOS has been found to play critical roles in the process of various cardiovascular diseases. Although NOS was first found to produce superoxide only when uncoupled with its cofactor or substrate, recent studies reveal that oxygen reduction to superoxide is an intrinsic process amid NO synthesis. Tetrahydrobiopterin plays a controlling role in preventing superoxide release from the eNOS oxygenase domain. Besides tetrahydrobiopterin, the regulation of eNOS uncoupling by the interactions with other proteins, protein phosphorylation, S-glutathionylation, and endogenous L-arginine derivatives, will be discussed in this review.

Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients With Type 2 Diabetes Mellitus

“…Induction of COX-2 and iNOS by inflammatory and apoptotic stimuli causes generation of reactive oxygen species and reduced nitric oxide availability. 23,24 Furthermore, adhesion molecules are important mediators of the inflammatory milieu triggering monocyte infiltration and foam cell formation. 15,25 Our findings strongly suggest that histone methyltransferase Set7 is critically involved in the pathophysiology of vascular dysfunction in patients with diabetes mellitus ( Figure 6).…”

Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance

“…The source of the superoxide may be NOS itself or superoxide generated from NOX or cytosolic xanthine oxidase, peroxisomal oxidases, or endoplasmic reticular oxidases. When NOS is uncoupled with its cofactor tetrahydrobiopterin or its substrate, arginine, there can be a massive increase in superoxide formation (36). Overproduction of NOS isoforms as a contributor to diabetic neuropathy has also been recently demonstrated (1) (Fig.…”

Maternal Vascular Physiology in Preeclampsia

“…22 NADPH oxidase and NOS uncoupling because of l-arginine deficiency contribute to superoxide generation in endothelial cells. 23 Treating human endothelial cells with l-arginine, Sankaralingam et al 10 demonstrated that in the presence of superoxide formation, l-arginine supplementation led to formation of peroxynitrite, which has been shown to be increased in the vasculature of women with preeclampsia. 24 In contrast, l-arginine supplementation after inhibition of oxidative stress did not result in peroxynitrite formation, 10 indicating that the oxidant status of the maternal environment may determine the efficacy of certain therapeutic interventions.…”