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(Circulation Research. 2007;101:648.)
© 2007 American Heart Association, Inc.

Editorials

How Does the Chloride/Proton Antiporter ClC-3 Control NADPH Oxidase?

Bernard Lassègue

From the Emory University School of Medicine, Division of Cardiology, Atlanta, Ga.

Correspondence to Bernard Lassègue, Emory University School of Medicine, Division of Cardiology, 1639 Pierce Drive, WMB, 319 Atlanta, GA 30322. E-mail bernard.lassegue@emory.edu

See related article, pages 663–671

Key Words: NADPH oxidase • ClC-3 • superoxide • Nox1 • Nox2

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

In this issue of Circulation Research, Miller and coworkers¹ introduce new concepts that drastically change current understanding of NADPH oxidase (Nox) regulation. Nox enzymes are important ubiquitous generators of reactive oxygen species (ROS) involved in a surprisingly varied array of functions such as immune defense and vascular pathophysiology.²

In their article, Miller et al start by demonstrating that Nox1 is localized in endosomes of vascular smooth muscle cells, and that it is stimulated by cytokines to generate ROS inside these vesicles, eventually leading to activation of NFB. This is an important demonstration of the intracellular activity of Nox1, and it is consistent with previous observations and speculations.² The most important finding of this work, however, is that Nox1 activity and signaling require ClC-3, a chloride/proton exchanger also localized in endosomes. Indeed, the authors show that chloride channel inhibitors and knockout of ClC-3 abolish cytokine-induced generation of ROS in endosomes and ROS-dependent NFB activation. This unexpected involvement of ClC-3 in Nox activation was first described in a recent article by the same group demonstrating that Nox2-mediated neutrophil functions are impaired in ClC-3 knockouts.³ The present study not only reveals the importance of ClC-3 in vascular tissue and its ability to control another Nox family member, but also challenges the prevalent theory of Nox activation.

The most straightforward way to explain the effect of ClC-3, which is favored by Miller and coworkers, is that this antiporter prevents Nox-induced accumulation of negative charges in the endosomal lumen. This function is . . . [Full Text of this Article]

Related Article:

Cytokine Activation of Nuclear Factor B in Vascular Smooth Muscle Cells Requires Signaling Endosomes Containing Nox1 and ClC-3

Francis J. Miller, Jr, Mohammed Filali, Gina J. Huss, Bojana Stanic, Ali Chamseddine, Thomas J. Barna, and Fred S. Lamb
Circ. Res. 2007 101: 663-671. [Abstract] [Full Text] [PDF]