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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1627.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase

Qian Zhang; Pulkit Malik; Deepesh Pandey; Sonali Gupta; Davin Jagnandan; Eric Belin de Chantemele; Botond Banfi; Mario B. Marrero; R. Daniel Rudic; David W. Stepp; David J.R. Fulton

From the Departments of Pharmacology, Physiology, and the Vascular Biology Center, Medical College of Georgia, Augusta.

Correspondence to David J.R. Fulton, PhD, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail dfulton{at}mcg.edu

Objectives— Increased formation of reactive oxygen species (ROS) has been identified as a causative factor in endothelial dysfunction by reducing NO bioavailability and uncoupling endothelial nitric oxide synthase (eNOS). However, the specific contribution of ROS to endothelial function is not well understood.

Methods and Results— A major source of intracellular ROS is the NADPH oxidase (Nox) family of enzymes. The goal of the current study was to directly assess the contribution of NADPH oxidase derived superoxide to eNOS function by expressing Nox5, a single gene product that constitutively produces superoxide within cells. Paradoxically, we found that instead of inhibiting eNOS, coexpression of Nox5 increased NO release from both bovine and human endothelial cells. To establish the functional significance of this observation in intact blood vessels, the endothelium of mouse aorta was transduced with Nox5 or control adenoviruses. Nox5 potently inhibited Ach-induced relaxation and potentiated contractile responses to phenylephrine. In precontracted aortae, acute exposure to superoxide dismutase induced significant vascular relaxation in vessels exposed to Nox5 versus control and unmasked the ability of Nox5 to activate eNOS in blood vessel endothelium.

Conclusions— These findings suggest that ROS inhibit eNOS function via consumption of NO rather than direct inhibition of enzymatic activity.

Key Words: nitric oxide • endothelial nitric oxide synthase • NADPH oxidase • endothelial cells • superoxide dismutase

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Targeted Increases in Endothelial Cell Superoxide Anion Production Stimulate eNOS-Dependent Nitric Oxide Production, Not Uncoupled eNOS Activity

Hao Xu and Kirkwood A. Pritchard, Jr
Arterioscler Thromb Vasc Biol 2008 28: 1580-1581. [Extract] [Full Text] [PDF]

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