Objective-The inhibition of oxidative stress is among the most relevant pleiotropic effects of statins. The mechanism by which statins exert their antioxidant effect in vivo is still undefined. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. Methods/Results-We developed an ELISA to evaluate serum levels of soluble-gp91 phox , the catalytic core of phagocyte NADPH oxidase. In a cross-sectional study performed in 30 hypercholesterolemic patients and in 20 controls, serum soluble-gp91 phox and urinary isoprostane, a marker of oxidative stress, were measured. The 2 variables were also measured in hypercholesterolemic patients, randomized to diet (nϭ15), or diet plus atorvastatin (10 mg daily, nϭ15) and followed for 30 days. Compared to controls, hypercholesterolemic patients had higher and significantly correlated (Rϭ0.71; PϽ0.001) serum soluble-gp91 phox (PϽ0.001) and urinary isoprostanes (PϽ0.001). After follow-up, the statin-allocated group showed a significant reduction of soluble-gp91 phox (Ϫ33%, PϽ0.01), that paralleled that of isoprostanes (Ϫ37%, PϽ0.01) and cholesterol (Ϫ25%, PϽ0.01). The diet-allocated group showed only a weak reduction of cholesterol. Key Words: gp91 phox Ⅲ oxidative stress Ⅲ hypercholesterolemia Ⅲ NADPH oxidase Ⅲ statins P rimary and secondary prevention trials with statins clearly demonstrated that this drug category is able to reduce cardiovascular events. 1,2 Even if the principal mechanism of action of statins is to lower cholesterol, other effects, the so-called pleiotropic effects, have been considered as adjunctive properties potentially accounting for the antiatherosclerotic effect of statins. 3 Inhibition of oxidative stress may be considered an intriguing pleiotropic effect in view of the fact that oxidative stress is thought to be a key event in the initiation and progression of atherosclerotic disease. 4 Reduction of several markers of oxidative stress including isoprostanes, 8-hydroxydeoxyguanosine (8-OHdG), and nitrotyrosine have been observed after statin treatment but the underlying mechanism is still unclear. [5][6][7][8][9] In a pilot study performed in patients with chronic granulomatous disease (X-CGD), a very rare life-threatening disease secondary to hereditary deficiency of gp91 phox (the catalytic subunit of phagocyte NADPH oxidase), we found a significant reduction of urinary isoprostanes. 10 Also, in children with hypercholesterolemia, we observed a significant correlation between platelet gp91 phox expression and urinary isoprostanes. 11 These previous observations suggest a role for the phagocyte NADPH oxidase, one of the most important cellular producers of superoxide anion (O 2 . ), 12 in the formation of this marker of oxidative stress. Because previous studies provided in vitro evidence that statins inhibit the expression and activation of NADPH oxidase, 6,13 we sought to analyze whether this occurs in vivo and ultimately contributes to the reduction of oxidative stress. Thus, we developed ...

Abstract-Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (ϩ18%) and high density lipoprotein cholesterol lower (Ϫ5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients Ͼ30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptordefective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the ⑀2 allele and a raising effect of the ⑀4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol.Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors. (Arterioscler Thromb Vasc Biol. 2000;20:e41-e52.)

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LDL-a treatment improved the plasma apo B 100-containing lipoproteins--LDL, Lp(a)--profile in a homozygote with a severe inherited disorder in which coronary artery atherosclerosis frequently has its clinical onset before 10 y of age. At the time of this report, no significant side effects had been observed.