Atorvastatin Inhibits gp91 ^phox Circulating Levels in Patients With Hypercholesterolemia

Abstract

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 ...

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

“…Statin treatment has been found to downregulate gp91 phox levels in human internal mammary arteries obtained from patients undergoing CABG (94). In a cross-sectional study, statin treatment of hyperlipidemic individuals was found to be associated with reduced circulating levels of gp91 phox , as well as markers of systemic oxidative stress (88). In the Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress (EPAS) trial, 49 patients undergoing scheduled CABG were randomized to placebo, pravastatin (40 mg/day), irbesartan (150 mg/day), or both for 4 weeks (69).…”

Immediate Antioxidant and Antiplatelet Effect of Atorvastatin via Inhibition of Nox2

“…12 The peptide was recognized by the specific monoclonal antibody against the amino acidic sequence (224 -268) of the extramembrane portion of Nox2 (catalytic core of NADPH oxidase), which was released in the medium on platelet activation. Values were expressed as picograms per milliliter; intra-assay and interassay coefficients of variation were 5.2% and 6%, respectively.…”

“…Serum levels of sNOX2-dp were detected by ELISA as previously described by Pignatelli et al 12 Blood samples were kept for 60 minutes at 37°C and centrifuged at 300g; serum was stored at Ϫ80°C. Values were expressed as picograms per milliliter; intraassay and interassay coefficients of variation were 5.2% and 6%, respectively.…”

Early Statin Therapy Within 48 Hours Decreased One-Year Major Adverse Cardiac Events in Patients With Acute Myocardial Infarction

“…An antioxidant effect, antiplatelet effect, and inhibition of smooth muscle cell proliferation have been suggested. [14][15][16] In patients with ACS, especially those undergoing PCI, early statin therapy has resulted in lower cardiovascular mortality and better angiographic profiles. [17][18][19] The efficacy of statins has been demonstrated in many clinical studies in AMI patients as well as in ACS patients.…”