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

Research output: Contribution to journalArticle

69 Scopus citations

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 RESULTSĝ€": 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. CONCLUSIONSĝ€": These findings suggest that ROS inhibit eNOS function via consumption of NO rather than direct inhibition of enzymatic activity.

Original languageEnglish (US)
Pages (from-to)1627-1633
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2008

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Keywords

  • Endothelial cells
  • Endothelial nitric oxide synthase
  • NADPH oxidase
  • Nitric oxide
  • Superoxide dismutase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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