gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension

Abstract

Background-Isoforms of the NADPH oxidase contribute to vascular superoxide anion ( · O 2 Ϫ ) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O 2 Ϫ to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction. Methods and Results-Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox Ϫ/Ϫ ) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox Ϫ/Ϫ mice (158Ϯ2 versus 149Ϯ2 mm Hg; PϽ0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox Ϫ/Ϫ mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox Ϫ/Ϫ mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox Ϫ/Ϫ mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice. Conclusions-These data indicate that the formation of O 2Ϫ by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

“…Recent studies suggest that in coronary arteries, NAD(P)H oxidases of the NOX family are a predominant source of O 2 −• from noninflammatory cells such as endothelium [48,49]. The formation of O 2 −• by the endothelial NADPH oxidase accounts for the reduced NO bioavailability, development of endothelial dysfunction from the aortic ring of gp91phox-knockout mice (gp91phox−/−) [50]. In this context, apocynin (4-hydroxy-3-methoxyacetophenonone) has been demonstrate to act as a potent and selective inhibitor of NADPH oxidase system in both in vitro and animal models [51][52][53] by interfering with the translocation of an essential cytosolic protein, p47phox [54][55][56].…”

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…Nox-derived ROS can also affect the local bioavailability of the vaso-protective signal molecule NO [61].…”

“…Nox2 accounts for significant ROS generation in vascular smooth muscle in resistance arteries [45] and in endothelium [42,76]. In a model of renovascular hypertension Nox2-derived superoxide decreased NO bioavailability, and there was marked protection from hypertension in the Nox2 (−/−) mice [61]. In low renin salt-sensitive hypertension, a tat-peptide inhibitor of Nox2 normalized ROS generation and endothelium-dependent vascular relaxation [77].…”

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Most experimental models of hypertension exhibit some degree of oxidative stress (48,67,93,95,236). Moreover, mice with reduced antioxidant enzyme systems and those deficient in NADPH oxidase have higher blood pressures than those with intact systems.…”