Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F ₂ -Isoprostane Formation in Hypercholesterolemic Subjects

Abstract

Background-Both statins and vitamin E, by reducing the rate of lipid peroxidation, may interfere with oxidative stress, but the impact of their combination is unknown. Methods and Results-We randomized 43 hypercholesterolemic patients (21 men, 22 women, age 63Ϯ11 years) to either simvastatin, to achieve Ͼ20% reduction of total cholesterol, or simvastatin plus 600 mg/d vitamin E for 2 months. Patients were then crossed over to the alternative treatment. Lipid parameters documented patients' compliance to simvastatin, whereas plasma levels of vitamin E documented compliance and absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso-prostaglandin F 2␣ (8-iso-PGF 2␣ ) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF 2␣ was significantly reduced by simvastatin, from 361Ϯ148 pg/mg creatinine (meanϮSD) at baseline to 239Ϯ124 pg/mg creatinine after 1 month.

Immediate Antioxidant and Antiplatelet Effect of Atorvastatin via Inhibition of Nox2

“…21,22 A reduction of urinary isoprostanes or an increase of circulating vitamin E has been observed after short-term (3 days) or long-term treatment with statins. [23][24][25] In the present study, using 2 markers of oxidative stress, ie, urinary isoprostanes and sNOX2-dp, we demonstrated that high-dose atorvastatin acutely decreases both markers, indicating that it exerts a rapid antioxidant effect. The parallel decrease of Nox2 activity and urinary isoprostanes reinforces data from previous studies suggesting a major role for Nox2 in the production of isoprostanes.…”

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

“…Experimental studies revealed that statins inhibit production of superoxide via the NADPH oxidase system in monocytes, 26 neutrophils, 27 and endothelial cells, 28 because activation of NADPH oxidase is dependent on an isoprenoid group, ie, geranyl geraniol, which derives from HMG-CoA and is thus inhibited by statins. 29 In parallel to these in vitro observations, De Caterina and coworkers 30 found a significant reduction of F2-isoprostane, a product of the attack of reactive oxygen species on esterified arachidonic acid, in patients with hypercholesterolemia who were receiving simvastatin. Statin therapy also lowers systemic levels of protein-bound nitrotyrosine, a marker for formation of peroxynitrite, ie, the end product of the reaction of superoxide with nitric oxide.…”

Urinary 8-iso-Prostaglandin F 2α as a Risk Marker in Patients With Coronary Heart Disease

“…This finding is of particular interest, because it has been demonstrated that intervention with statins in mildly hypercholesterolemic patients reduced oxidant burden, ie, 8-iso-PGF 2␣ and 3-nitrotyrosine formation. 20,21 However, our trial was designed as a case-control study and therefore was not intended to detect such effects. Recently, a difference in urinary 8-iso-PGF 2␣ in CHD patients with 1-vessel and multivessel disease was found.…”