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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2585.)
© 2006 American Heart Association, Inc.

Editorials

Coupling eNOS Uncoupling to the Innate Immune Response

Ton J. Rabelink; Anton-Jan van Zonneveld

From the Department of Nephrology and Hypertension, Leiden University Medical Center, the Netherlands.

Correspondence to Ton J. Rabelink, Department of Nephrology and Hypertension, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail t.rabelink@lumc.nl

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

The endothelial isoform of nitric oxide synthase (eNOS) has been well recognized for its central role in conserving vascular homeostasis by inducing quiescence of endothelial cells and adjacent vessel wall structures. For example, eNOS-derived NO can alter protein function by S-nitrosylation of cysteine residues and, in endothelial cells, patterns of S-nitrosylated transcriptional regulators have been shown to interrupt inflammatory signaling and induce cell cycle arrest.¹ Likewise, by competing with oxygen as an electron acceptor at complex IV, NO can limit energy expenditure through reducing oxidative phosphorylation during episodes of hypoxic challenge.²

See page 2688

Yet eNOS has also been recognized as a source of non-nitrous reactive oxygen species that can elicit a coordinated proinflammatory response. This is related to the basic chemistry in the enzyme where NADPH-derived electrons flow from the reductase domain toward the oxygenase domain. With the cofactor calmodulin bound to the native homodimeric enzyme, and in the presence of tetrahydrobiopterin (BH4), these electrons react with oxygen and L-arginine and lead to the formation of L-citrulline and NO.³ However, if either one of these factors is (relatively) lacking, oxidation of oxygen occurs and the enzyme subsequently releases superoxide.^3,4 This phenomenon, the so-called "uncoupling" of the eNOS, appears to be strongly conserved throughout evolution. It is therefore likely that this is not so much an anomaly of the enzyme but part of its physiological role in vascular homeostasis. As we recently proposed, activation of the innate immune system may probably lead to such uncoupling of the enzyme thus placing . . . [Full Text of this Article]

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