Hereditary Deficiency of gp91 phox Is Associated With Enhanced Arterial Dilatation

Abstract

Background— NADPH oxidase is believed to modulate arterial tone, but its role in humans is still unclear. The objective of this study was to evaluate whether NADPH oxidase is involved in flow-mediated arterial dilation (FMD). Methods and Results— Twenty-five patients with hereditary deficiency of gp91 phox , the catalytic core of NADPH oxidase, (X-CGD), 25 healthy subjects, and 25 obese patients matched for sex and age were recruited. FMD, platelet gp91 phox , serum levels of nitrite and nitrate as markers of nitric oxide generation, oxidized low-density lipoprotein, and urinary excretion of isoprostanes as markers of oxidative stress were determined. Platelet gp91 phox expression was downregulated in X-CGD patients (1.0±0.8 mean fluorescence; P <0.001) and upregulated in obese patients (4.1±2.2 mean fluorescence; P =0.01) compared with healthy subjects (2.9±1.7 mean fluorescence). Urinary excretion of isoprostanes was reduced in X-CGD patients (41.7±33.3 pg/mg creatinine; P =0.04) and increased in obese patients (154.4±91 pg/mg creatinine; P <0.001) compared with healthy subjects (69.5±52.4 pg/mg creatinine). Obese patients had higher serum oxidized low-density lipoprotein than healthy subjects (35.3±6.7 versus 24.8±9.8 U/L; P <0.001) and X-CGD patients (28.5±7.2 U/L; P <0.001). X-CGD patients had significantly higher FMD (14.7±5.9%) compared with healthy subjects (7.9±2.5%; P <0.001); obese patients had lower FMD (5.3±3.0%; P =0.028) compared with healthy subjects. Serum nitrite and nitrate levels were significantly higher in patients with X-CGD (36.0±10.8 μmol/L; P =0.016) and lower in obese patients (9.3±11.0 μmol/L; P =0.001) compared with healthy subjects (27.1±19.1 μmol/L). Serum nitrite and nitrate levels significantly correlated with FMD ( R s =0.403, P <0.001) and platelet gp91 phox ( R s =−0.515, P <0.001). FMD inversely correlated with platelet gp91 phox ( R s =−0.502, P <0.001) and isoprostanes ( R s =−0.513, P <0.001). Conclusion— This study provides the first evidence that, in humans, gp91 phox is implicated in the modulation of arterial tone.