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Paradoxical Activation of Endothelial Nitric Oxide Synthase (eNOS) by NADPH Oxidase 5
Author(s) -
Zhang Qian,
Gupta Sonali,
Rudic R. Daniel,
Stepp David W,
Fulton David JR
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a525-c
Subject(s) - enos , superoxide , nitric oxide , nitric oxide synthase , nadph oxidase , endothelium , chemistry , vasodilation , nitric oxide synthase type iii , endothelial dysfunction , phenylephrine , superoxide dismutase , medicine , endocrinology , biochemistry , biology , reactive oxygen species , oxidative stress , enzyme , blood pressure
Increased superoxide formation in endothelial cells (ECs) has been identified as a causative factor in endothelial dysfunction by reducing nitric oxide (NO) bioavailability and uncoupling endothelial nitric oxide synthase (eNOS). However, the specific contribution of ROS to endothelial function in the absence of other disease variables is not well understood. The current goal was to directly assess the contribution of NADPH oxidase derived superoxide to eNOS function by expressing Nox5, a single gene that produces intracellular superoxide. Paradoxically, we found that Nox5 increased eNOS activity in both co‐transfected COS‐7 cells and adenovirally transduced bovine aortic ECs as determined by the detection of NO metabolites. Nox5 also activated eNOS in human aortic ECs as detected by a cGMP reporter assay that measures the release of biologically active NO from cells in the presence of superoxide dismutase (SOD). To establish the functional significance of this observation in blood vessels, the endothelium of mouse aorta was transduced with control or Nox5 adenoviruses. Nox5 potently inhibited Ach‐induced relaxation and potentiated the contractile responses to phenylephrine. In precontracted blood vessels, acute exposure to SOD induced significant vascular relaxation in vessels exposed to Nox5 versus control and unmasked the ability of Nox5 to activate eNOS in blood vessel endothelium.