Martino Francesco, Loffredo Lorenzo, Carnevale Roberto, Sanguigni Valerio, Martino Eliana, Catasca Elisa, Zanoni Cristina, Pignatelli Pasquale, Violi Francesco
IV Divisione di Clinica Medica, Viale del Policlinico 155, Rome, 00161, Italy.
Pediatrics. 2008 Sep;122(3):e648-55. doi: 10.1542/peds.2008-0735.
Endothelial dysfunction and intima-media thickness are precocious manifestations of hypercholesterolemia, but the mechanism is unclear.
The aim of the study was to analyze the interplay among endothelial dysfunction, intima-media thickness, and oxidative stress in children with hypercholesterolemia.
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.
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.
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.
内皮功能障碍和内膜中层厚度是高胆固醇血症的早熟表现，但其机制尚不清楚。
本研究旨在分析高胆固醇血症患儿内皮功能障碍、内膜中层厚度和氧化应激之间的相互作用。
我们进行了一项横断面研究，比较了50名高胆固醇血症患儿（平均年龄±标准差：10.0±3.7岁）和50名无高胆固醇血症患儿（平均年龄：9.2±3.5岁）的血流介导的血管舒张、内膜中层厚度、血脂谱、作为氧化应激标志物的尿异前列腺素以及血小板中烟酰胺腺嘌呤二核苷酸磷酸氧化酶催化亚基gp91(phox)的表达。还研究了4名gp91(phox)遗传性缺陷患儿。
与对照组相比，高胆固醇血症患儿的血流介导的血管舒张降低（平均±标准差：6.2±2.4%对9.2±2.5%），内膜中层厚度增加（0.45±0.07对0.40±0.06mm），尿异前列腺素增加（86.9±51.6对45.9±25.6pg/mg肌酐），血小板gp91(phox)表达增加（平均荧光强度4.4±3.8对2.0±1.7）。在双变量分析中，血流介导的血管舒张与低密度脂蛋白胆固醇、内膜中层厚度、尿异前列腺素和血小板gp91(phox)相关。逐步多元线性回归分析表明，在高胆固醇血症患儿中，血流介导的血管舒张和内膜中层厚度与低密度脂蛋白胆固醇和尿异前列腺素显著相关；此外，血小板gp91(phox)表达是尿异前列腺素的独立预测因子。gp91(phox)遗传性缺陷患儿表现出血小板gp91(phox)下调和尿异前列腺素排泄减少。
该研究表明，gp91(phox)介导的氧化应激可能在过早发生动脉粥样硬化的儿童动脉壁的解剖和功能变化中起致病作用。
