Antioxidative Potential of Fluvastatin <i>via</i> the Inhibition of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase Activity

Abstract

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis.1-3) Elevated oxidative stress and superoxide anion generation could promote the conversion of low density lipoprotein (LDL) to atherogenic oxidized LDL (ox-LDL), contributing to atherosclerosis. There is increasing evidence that the oxidative modification of LDL contributes to the formation of foam cells in the artery wall. 4) Concerning the modification of LDL, neutrophils rapidly take up ox-LDL and generate superoxide anions, which may cause superoxide mediated lipid peroxidation in vivo.5) The superoxide anions of human monocytes participate in both the oxidation of LDL and its conversion to a cytotoxin. 6)We had reported that fluvastatin, a strong inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the late limiting enzyme of cholesterol biosynthesis, suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition, unrelated to its strong hypocholesterolemic action.7) Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important and major source of superoxide anions in neutrophils. 8)Thus, the aim of this study was to determine the direct effect of fluvastatin on the NADPH oxidase activity in neutrophils using phorbor 12-myristate 13-acetate (PMA) as a stimulant to clarify the strong anti-atherosclerotic effect without serum lipid reduction. PMA activates protein kinase C (PKC) directly, and PKC activity is primarily cytosolic in unstimulated neutrophils, but becomes firmly associated with the membrane fraction after PMA treatment.9) The effects of fluvastatin on NADPH oxidase activity were also compared with those of another HMG-CoA reductase inhibitor, pravastatin, which is known as a highly hepatocyte-selective agent in inhibiting cholesterol synthesis. Preparation of Neutrophils Neutrophils were obtained from 6-week-old male Wistar rats 16 h after an intraperitoneal injection of 2% casein solution at a dosage of 1/10 the body weight, as described by Morimoto et al. 11) After 16 h, migrated neutrophils were collected by an intraperitoneal injection of 50 ml calcium-free 0.9% NaCl solution containing 10 mM phosphate buffer (pH 7.4), 6 mM KCl, and 1 mM MgCl 2 (Krebs-Ringer phosphate buffer solution, KRP). The neutrophils were washed 3 times with KRP solution by cen- Key words fluvastatin; nicotinamide adenine dinucleotide phosphate oxidase; antioxidant; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor 10) MATERIALS AND METHODS Chemicals

Early Administration of Fluvastatin, but not at the Onset of Ischemia or Reperfusion, Attenuates Myocardial Ischemia-Reperfusion Injury Through the Nitric Oxide Pathway Rather Than Its Antioxidant Property

“…21 The antioxidant action of statins is derived not only from the reduction of oxidized low-density lipoprotein, but from inhibition of NADPH oxidase, which generates superoxide anion (·O2 -) in the vascular wall. 22 FV has a potent antioxidant property as a free radical scavenger, because of its unique chemical structure, 17 but in the present study, however, FV did not reduce the myocardial content of 8-OHdG, which is produced by hydroxylation at the C-8 position of deoxyguanosine by ·OH and is currently used as a stable biomarker of oxidative DNA damage. 18,23 Formation of 8-OHdG in the heart with IR progressively increases after reperfusion and is completely blocked by co-treatment with a free radical scavenger.…”

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

“…In those studies, 14,15 LPS-induced hyporeactivity to ACh and to different vasoconstrictors could be reversed by intra-arterial infusion of high doses of the antioxidant vitamin C. Despite the lack of a direct antioxidative effect, statins may inhibit key proteins involved in generation of reactive oxygen species. 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.…”

Effect of pravastatin on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine in rat aorta1

“…Another potential mechanism by which pravastatin improved endothelial function is by reducing the oxidative inactivation of NO. Recent investigations have demonstrated that statins can decrease lipid peroxidation production [7] , suppress NADPH oxidase activity [28] , and increase the activity of catalase [29] , and superoxide dismutase [7] , which decreases the generation of oxygen free radicals resulting in reduction of NO activation. Moreover, a number of studies have shown that pravastatin can also reduce superoxide anion production by suppressing PKC activity in vascular cells [14,15] .…”