Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 31, Issue 6, Pages 1368-U302Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.219238
Keywords
blood pressure; endothelial function; reactive oxygen species; vasodilation; NADPH oxidase
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Funding
- British Heart Foundation [RG/08/011/25922, CH/99001, RE/08/003]
- Fondation Leducq
- European Union [LSHM-CT-2005-018833]
- British Heart Foundation
- British Heart Foundation [RG/08/011/25922, PG/09/102/28133, PG/10/98/28655, PG/08/110/26228] Funding Source: researchfish
- Medical Research Council [G1000458, G0700320, G0600785] Funding Source: researchfish
- MRC [G0600785, G1000458, G0700320] Funding Source: UKRI
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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 (H2O2), 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 H2O2 production and H2O2-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 H2O2 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. (Arterioscler Thromb Vasc Biol. 2011;31:1368-1376.)
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