Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo

Robin Ray, Colin E. Murdoch, Minshu Wang, Celio X. Santos, Min Zhang, Sara Alom-Ruiz, Narayana Anilkumar, Alexandre Ouattara, Alison C. Cave, Simon J. Walker, David J. Grieve, Rebecca L. Charles, Philip Eaton, Alison C. Brewer, Ajay M. Shah

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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 O ), but its role in vivo remains unclear.

Methods and 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 O production and H O -induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants.
Conclusion: Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H O 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.
Original languageEnglish
Pages (from-to)1368-1376
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number6
Early online date18 May 2011
DOIs
Publication statusPublished - Jun 2011

Keywords

  • blood pressure
  • endothelial function
  • reactive oxygen species vasodilation
  • NADPH oxidase

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    Ray, R., Murdoch, C. E., Wang, M., Santos, C. X., Zhang, M., Alom-Ruiz, S., Anilkumar, N., Ouattara, A., Cave, A. C., Walker, S. J., Grieve, D. J., Charles, R. L., Eaton, P., Brewer, A. C., & Shah, A. M. (2011). Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(6), 1368-1376. https://doi.org/10.1161/ATVBAHA.110.219238