Coupled and Uncoupled NOS: Separate But Equal?

Abstract

See related article, pages 768–776 Endothelial dysfunction is seen early in the development of atherosclerosis, before overt vascular and structural changes. Nitric oxide (NO) is recognized as one of the major mediators of the maintenance of vascular homeostasis, and a decrease in NO bioavailability is associated with endothelial dysfunction. Endothelial NO synthase (eNOS; NOS3) catalyzes the formation of NO from L-arginine and O2 in a reaction requiring Ca2+–calmodulin, FAD, FMN, NADPH, and tetrahydrobiopterin (BH4). A decrease in NO bioavailability may be caused by: (1) a decrease in the expression or activity of NOS3, (2) uncoupling of NOS to produce superoxide (O2·−), or (3) degradation of NO by reacting with O2·− from other enzymatic sources resulting in the formation of peroxynitrite (ONOO−). Physiologically, NOS3-derived NO inhibits leukocyte–endothelial cell adhesion, vascular smooth muscle proliferation and migration, and platelet aggregation to maintain the health of the vascular endothelium. Under a number of pathological conditions, NOS3 enzymatic activity becomes uncoupled, resulting in the production of O2·−. NOS3-derived O2·− has been shown to contribute to the development and progression of atherosclerosis and hypertension.1,2 In this issue of Circulation Research , Gharavi et al report that treatment of endothelial cells with oxidized phospholipids results in increased interleukin-8 (IL-8) production through the activation and uncoupling of NOS3.3 When NOS is uncoupled, electrons flowing from the reductase domain to the heme are diverted to molecular oxygen instead of to L-arginine, resulting in the formation of O2·−. A number of potential mechanisms are responsible for uncoupling of NOS3, although the most consistent evidence exists for BH4 deficiency.4,5 Also, NOS3 uncoupling …