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CLINICAL RESEARCH: HEART DISEASE IN CHILDREN

Early Increase of Oxidative Stress and Soluble CD40L in Children With Hypercholesterolemia

Francesco Martino, MD^_*,_*, Pasquale Pignatelli, MD, Eliana Martino, MD^_*, Francesco Morrone, MD^_*, Roberto Carnevale, PhD, Serena Di Santo, PhD, Barbara Buchetti, PhD, Lorenzo Loffredo, MD and Francesco Violi, MD

^_* Center of Clinic Lipid Research, Department of Pediatrics, University of Rome "La Sapienza," Rome, Italy
Department of Experimental Medicine and Pathology, University of Rome "La Sapienza," Rome, Italy.

Manuscript received November 6, 2006; revised manuscript received January 16, 2007, accepted January 23, 2007.

^_* Reprint requests and correspondence: Dr. Francesco Violi, IV Divisione di Clinica Medica, Viale del Policlinico 155, Rome 00161, Italy. (Email: francesco.violi{at}uniroma1.it).

Objectives: The aim of the study was to analyze the behavior of oxidative stress and its interplay with CD40L, a protein that is implicated in atherosclerosis, in hypercholesterolemic children.

Background: Oxidative stress has been suggested to play a major role in premature atherosclerosis.

Methods: Forty-one children with hypercholesterolemia (mean age 9.28 ± 0.5 years) and 40 children with normocholesterolemia (mean age 9.02 ± 0.69 years) were matched for gender and age. Within each group, children were classified as having or not having a family history of cardiovascular disease. Serum levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, and plasma levels of soluble CD40L (sCD40L) were measured in each child. In a subgroup of children with high (n = 8) or normal (n = 8) levels of serum cholesterol, platelet p38 mitogen-activated protein (MAP) kinase phosphorylation, a protein involved in the activation of nicotinamide adenine dinucleotide phosphate oxidase, was determined.

Results: Children with hypercholesterolemia had higher values of 8-OHdG and sCD40L compared with control subjects (0.55 ± 0.06 ng/ml vs. 0.21 ± 0.02 ng/ml, p < 0.001 and 0.55 ± 0.04 ng/ml vs. 0.19 ± 0.03 ng/ml, p < 0.001, respectively). A significant correlation between 8-OHdG and sCD40L was observed in children with high (r = 0.676, p < 0.001) or normal (r = 0.878, p < 0.001) levels of cholesterol. Children with a family history of cardiovascular disease tended to have higher values of 8-OHdG and sCD40L, but the difference was not significant. Analysis of platelet p38 MAP kinase showed that it was phosphorylated more in children with hypercholesterolemia compared with control subjects (36.8 ± 5.8 AU vs. 8.0 ± 4.5 AU, p < 0.001 respectively).

Conclusions: Children with hypercholesterolemia have an early increase of oxidative stress that may be responsible for up-regulation of CD40L and potentially predispose to premature atherosclerosis.

Abbreviations and Acronyms   8-OHdG = 8-hydroxy-2'-deoxyguanosine   LDL = low-density lipoprotein   sCD40L = soluble CD40L   TC = total cholesterol

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