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

TY - JOUR

T1 - Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo

AU - Ray, Robin

AU - Murdoch, Colin E

AU - Wang, Minshu

AU - Santos, Celio X

AU - Zhang, Min

AU - Alom-Ruiz, Sara

AU - Anilkumar, Narayana

AU - Ouattara, Alexandre

AU - Cave, Alison C

AU - Walker, Simon J

AU - Grieve, David J

AU - Charles, Rebecca L

AU - Eaton, Philip

AU - Brewer, Alison C

AU - Shah, Ajay M

PY - 2011/6

Y1 - 2011/6

N2 - 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.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(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.CONCLUSION: 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.

AB - 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.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(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.CONCLUSION: 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.

KW - Angiotensin II/pharmacology

KW - Animals

KW - Blood Pressure

KW - Endothelium, Vascular/enzymology

KW - Hydrogen Peroxide/metabolism

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - NADPH Oxidase 4

KW - NADPH Oxidases/physiology

KW - Nitric Oxide/physiology

KW - Reactive Oxygen Species/metabolism

KW - Vasodilation

U2 - 10.1161/ATVBAHA.110.219238

DO - 10.1161/ATVBAHA.110.219238

M3 - Article

C2 - 21415386

VL - 31

SP - 1368

EP - 1376

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 6

ER -