Published online September 1, 2008
PEDIATRICS Vol. 122 No. 3 September 2008, pp. e648-e655 (doi:10.1542/10.1542/peds.2008-0735)
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ARTICLE

Oxidative Stress Is Associated With Arterial Dysfunction and Enhanced Intima-Media Thickness in Children With Hypercholesterolemia: The Potential Role of Nicotinamide-Adenine Dinucleotide Phosphate Oxidase

Francesco Martino, MDa, Lorenzo Loffredo, MDb, Roberto Carnevale, PhDb, Valerio Sanguigni, MDc, Eliana Martino, MDa, Elisa Catasca, MSa, Cristina Zanoni, MSa, Pasquale Pignatelli, MDb and Francesco Violi, MDb

a Center of Clinic Lipid Research, Department of Pediatrics
b Division of Internal Medicine H, Department of Experimental Medicine, University of Rome "La Sapienza," Rome, Italy
c Department of Internal Medicine, University of Rome "Tor Vergata," Rome, Italy

BACKGROUND. Endothelial dysfunction and intima-media thickness are precocious manifestations of hypercholesterolemia, but the mechanism is unclear.

OBJECTIVE. The aim of the study was to analyze the interplay among endothelial dysfunction, intima-media thickness, and oxidative stress in children with hypercholesterolemia.

METHODS. We performed a cross-sectional study comparing flow-mediated dilation, intima-media thickness, lipid profile, urinary isoprostanes as markers of oxidative stress, and platelet expression of gp91phox, the catalytic unit of nicotinamide-adenine dinucleotide phosphate oxidase, in a population of 50 children with hypercholesterolemia (mean age ± SD: 10.0 ± 3.7 years) and 50 children without hypercholesterolemia (mean age: 9.2 ± 3.5 years). Four children with hereditary deficiency of gp91phox were studied also.

RESULTS. Children with hypercholesterolemia had reduced flow-mediated dilation (mean ± SD: 6.2 ± 2.4 vs 9.2 ± 2.5%) and enhanced intima-media thickness (0.45 ± 0.07 vs 0.40 ± 0.06 mm), urinary isoprostanes (86.9 ± 51.6 vs 45.9 ± 25.6 pg/mg creatinine), and gp91phox platelet expression (4.4 ± 3.8 vs 2.0 ± 1.7 mean fluorescence) compared with control subjects. At bivariate analysis, flow-mediated dilation was correlated with low-density lipoprotein cholesterol, intima-media thickness, urinary isoprostanes, and platelet gp91phox. Stepwise multiple linear regression analysis showed that, in children with hypercholesterolemia, flow-mediated dilation and intima-media thickness were significantly associated with low-density lipoprotein cholesterol and urinary isoprostanes; also, gp91phox platelet expression was an independent predictor of urinary isoprostanes. Children with gp91phox hereditary deficiency showed downregulation of platelet gp91phox and reduced urinary excretion of isoprostanes.

CONCLUSIONS. The study suggests that gp91phox-mediated oxidative stress may have a pathogenic role in the anatomic and functional changes of the arterial wall occurring in children with premature atherosclerosis.

Key Words: atherosclerosis • hypercholesterolemia • oxidative stress • flow-mediated dilation • gp91phox

Abbreviations: TC—total cholesterol • LDL—low-density lipoprotein • IMT—intima-media thickness • HC—children with hypercholesterolemia • FMD—flow-mediated dilation • NO—nitric oxide • ROS—reactive oxygen species • NADPH—nicotinamide-adenine dinucleotide phosphate • NC—children without hypercholesterolemia • IgG—immunoglobulin G • FITC—fluorescein isothiocyanate • X-CGD—X-linked chronic granulomatous disease

Accepted May 14, 2008.


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