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.

Abstract

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 gp91(phox), 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 gp91(phox) 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 gp91(phox) 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 gp91(phox). 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, gp91(phox) platelet expression was an independent predictor of urinary isoprostanes. Children with gp91(phox) hereditary deficiency showed downregulation of platelet gp91(phox) and reduced urinary excretion of isoprostanes.

CONCLUSIONS:

The study suggests that gp91(phox)-mediated oxidative stress may have a pathogenic role in the anatomic and functional changes of the arterial wall occurring in children with premature atherosclerosis.

• Authors: Francesco Martino, Lorenzo Loffredo, Roberto Carnevale, Valerio Sanguigni, Eliana Martino, Elisa Catasca, Cristina Zanoni, Pasquale Pignatelli, Francesco Violi
• Journal: Pediatrics (Pediatrics) Vol. 122 Issue 3 Pg. e648-55 (Sep 2008) ISSN: 1098-4275 [Electronic] United States
• PMID: 18762499 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Glycoproteins
• Cholesterol
• CYBB protein, human
• NADPH Oxidase 2
• NADPH Oxidases

Topics

• Adolescent
• Blood Platelets (metabolism)
• Carotid Arteries (diagnostic imaging, physiopathology)
• Child
• Child, Preschool
• Cholesterol (blood)
• Cross-Sectional Studies
• Female
• Flow Cytometry
• Granulomatous Disease, Chronic (blood, metabolism)
• Humans
• Hypercholesterolemia (diagnostic imaging, enzymology, physiopathology)
• Immunoenzyme Techniques
• Male
• Membrane Glycoproteins (biosynthesis, blood)
• NADPH Oxidase 2
• NADPH Oxidases (biosynthesis, blood)
• Oxidative Stress (physiology)
• Risk Factors
• Tunica Intima (diagnostic imaging)
• Ultrasonography