on October 5, 2009
Published online before print October 5, 2009, doi: 10.1161/CIRCULATIONAHA.109.877191
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Submitted on May 2, 2009
From the Department of Experimental Medicine, Divisione I Clinica Medica (F.V., R.C., P.P., S.B., L.L.), and Center of Clinic Lipid Research, Department of Pediatrics (F.M.), University of Rome "La Sapienza," Rome; Department of Internal Medicine, University of Rome "Tor Vergata," Rome (V.S., P.R., A.F.); Department of Pediatrics and Institute of Molecular Medicine "A. Nocivelli," University of Brescia, Brescia (A.P., A.R.S.); Department of Pediatrics, University of Naples, Naples (C.P.); Department of Biomedicine and Evolutive Aging, University of Bari, Bari (D.D.M., B.M.); IRCSS Foundation, University of Milan, Milan (M.C.P.); Department of Pediatrics, University of Turin, Turin (S.M.); and Department of Pediatrics, University of Florence, Florence (E.G.). * To whom correspondence should be addressed. E-mail: francesco.violi{at}uniroma1.it.
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 gp91phox, the catalytic core of NADPH oxidase, (X-CGD), 25 healthy subjects, and 25 obese patients matched for sex and age were recruited. FMD, platelet gp91phox, 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 gp91phox 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 (Rs=0.403, P<0.001) and platelet gp91phox (Rs=-0.515, P<0.001). FMD inversely correlated with platelet gp91phox (Rs=-0.502, P<0.001) and isoprostanes (Rs=-0.513, P<0.001). Conclusion—This study provides the first evidence that, in humans, gp91phox is implicated in the modulation of arterial tone.
Accepted on July 31, 2009
Hereditary Deficiency of gp91phox Is Associated With Enhanced Arterial Dilatation. Results of a Multicenter Study
Francesco Violi MD*,
Key words: atherosclerosis • gp91phox protein, human • oxidative stress
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