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(Circulation Research. 2006;98:717.)
© 2006 American Heart Association, Inc.

Editorial

Coupled and Uncoupled NOS: Separate But Equal?

Uncoupled NOS in Endothelial Cells Is a Critical Pathway for Intracellular Signaling

Jennifer C. Sullivan, Jennifer S. Pollock

From the Vascular Biology Center, Medical College of Georgia, Augusta.

Correspondence to Jennifer S. Pollock, PhD, CB 3213B, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912. E-mail jpollock@mcg.edu

See related article, pages 768–776

Key Words: nitric oxide • superoxide • nitric oxide synthase • endothelial cells

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
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, . . . [Full Text of this Article]

Related Article:

Role of Endothelial Nitric Oxide Synthase in the Regulation of SREBP Activation by Oxidized Phospholipids

Nima M. Gharavi, Nancy A. Baker, Kevin P. Mouillesseaux, Winnie Yeung, Henry M. Honda, Xavier Hsieh, Michael Yeh, Eric J. Smart, and Judith A. Berliner
Circ. Res. 2006 98: 768-776. [Abstract] [Full Text] [PDF]

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