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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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