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

doi:10.1161/ATVBAHA.108.168278

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Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase

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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, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.28(9), pp.1627-1633

09/2008

DOI: 10.1161/ATVBAHA.108.168278

PMCID: PMC2771553

PMID: 18556569

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Abstract

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.

Details

Title: Subtitle: Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase
Creators: Qian Zhang - Prevention Institute
Pulkit Malik - Prevention Institute
Deepesh Pandey - Prevention Institute
Sonali Gupta - Prevention Institute
Davin Jagnandan - Prevention Institute
Eric Belin de Chantemele - From the Departments of Pharmacology, Physiology, and the Vascular Biology Center, Medical College of Georgia, Augusta
Botond Banfi - Prevention Institute
Mario B. Marrero - Augusta University
R. Daniel Rudic - Pharmacology and Toxicology
David W. Stepp - Augusta University
David J.R. Fulton - From the Departments of Pharmacology, Physiology, and the Vascular Biology Center, Medical College of Georgia, Augusta
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.28(9), pp.1627-1633
DOI: 10.1161/ATVBAHA.108.168278
PMID: 18556569
PMCID: PMC2771553
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Language: English
Date published: 09/2008
Academic Unit: Anatomy and Cell Biology; Otolaryngology; Internal Medicine
Record Identifier: 9984284451502771

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