title: Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo.
abstract: OBJECTIVE
  Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H(2)O(2)), but its role in vivo remains unclear.
  
  
  RESULTS
  We generated transgenic mice with endothelium-targeted Nox4 overexpression (Tg) to study the in vivo role of Nox4. Tg demonstrated significantly greater acetylcholine- or histamine-induced vasodilatation than wild-type littermates. This resulted from increased H(2)O(2) production and H(2)O(2)-induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants.
  
  
  CONCLUSIONS
  Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H(2)O(2) production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Our results suggest that therapeutic strategies to modulate ROS production in vascular disease may need to separately target individual Nox isoforms.
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Ray
authors.forename: Colin E
authors.initials: CE
authors.lastname: Murdoch
authors.forename: Minshu
authors.initials: M
authors.lastname: Wang
authors.forename: Celio X
authors.initials: CX
authors.lastname: Santos
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Sara
authors.initials: S
authors.lastname: Alom-Ruiz
authors.forename: Narayana
authors.initials: N
authors.lastname: Anilkumar
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ouattara
authors.forename: Alison C
authors.initials: AC
authors.lastname: Cave
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Walker
authors.forename: David J
authors.initials: DJ
authors.lastname: Grieve
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Charles
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse