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NADPH oxidases (Noxs) are reactive oxygen species-generating enzymes implicated in cardiovascular disease. Nox4 is the most abundantly expressed isoform in endothelial cells but its function remains unknown. We investigated the role of endothelial Nox4 on vascular function and blood pressure (BP) in vivo.
Methods and Results
We generated transgenic mice with endothelium-specific overexpression of Nox4 (Nox4TG) and studied the effects on endothelial function (aortic rings ex vivo) and blood pressure (telemetry). Nox4 protein levels were twofold higher in Nox4TG aorta compared with wild-type (wt) littermates, with no changes in the expression of other Nox isoforms. Nox4TG had enhanced relaxation to acetylcholine (ACh) compared with wt mice (−log EC50 7.76Â±0.07 vs 7.20Â±0.05; n=12; p<0.001) but similar relaxation to sodium nitroprusside. The ACh response in Nox4TG and wt mice was dentical in the presence of catalase (1500 U/ml) or with high extracellular potassium (30 mM) pre-contraction, but remained greater in Nox4TG in the presence of inhibitors of nitric oxide synthesis (l-NMMA, 100Â μM), soluble guanylate cyclase (ODQ, 5Â μM) or protein kinase G (KT5823, 2Â μM). Ox4TG also had significantly lower BP than wt mice (mean BP 102.5Â±1.8 vs 109.5Â±2.0 mm Hg; n=10; p=0.05), which was abolished after chronic treatment with N-acetylcysteine or an OD/catalase imetic, EUK-8. Plasma nitrite/nitrate levels and aortic levels of phosphorylated VASP were identical and acute intravenous treatment with l-NMMA (10 mg/kg) increased BP to a similar extent in Nox4TG and wt mice. The hypertensive response to chronic 14-day angiotensin II infusion (1.1 mg/kg per day) was lower in ox4TG compared with wt mice (mean BP 116.7Â±4.7 vs 129.4Â±3.5 mm Hg; n=10; p<0.05).
Nox4TG had significantly enhanced ACh-induced vasodilatation compared with wt mice as a result of hydrogen peroxide-induced hyperpolarisation. Nox4TG also had a lower BP, which was not attributable to altered nitric oxide bioactivity but was normalised by chronic antioxidant treatment. These results suggest that endothelial Nox4 has potentially beneficial effects on vascular tone and BP.