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(Circulation. 2009;120:1616-1622.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Hereditary Deficiency of gp91^phox Is Associated With Enhanced Arterial Dilatation

Results of a Multicenter Study

Francesco Violi, MD; Valerio Sanguigni, MD; Roberto Carnevale, PhD; Alessandro Plebani, MD; Paolo Rossi, MD; Andrea Finocchi, MD; Claudio Pignata, MD; Domenico De Mattia, MD; Baldassarre Martire, MD; Maria Cristina Pietrogrande, MD; Silvana Martino, MD; Eleonora Gambineri, MD; Anna Rosa Soresina, MD; Pasquale Pignatelli, MD; Francesco Martino, MD; Stefania Basili, MD; Lorenzo Loffredo, MD

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.).

Correspondence to Professor Francesco Violi, Divisione I Clinica Medica, Viale del Policlinico 155, Roma, 00161, Italy. E-mail francesco.violi{at}uniroma1.it

Received May 2, 2009; accepted July 31, 2009.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1553-1554. [Extract] [Full Text]