Oxidized low-density lipoprotein (Ox-LDL) has been studied for over 25 years. Numerous pro- and anti-atherogenic properties have been attributed to Ox-LDL. Yet, Ox-LDL has neither been defined nor characterized, as its components and composition change depending on its source, method of preparation, storage, and use. It contains unoxidized and oxidized fatty acid derivatives both in the ester and free forms, their decomposition products, cholesterol and its oxidized products, proteins with oxidized amino acids and cross-links, and polypeptides with varying extents of covalent modification with lipid oxidation products, and many others. It seems to exist in vivo in some form not yet fully characterized. Until its pathophysiological significance, and how it is generated in vivo are determined, the nature of its true identity will be only of classical interest. In this review, its components, their biological actions and methods of preparation will be discussed.

Objective-The cytosolic form of Cu/Zn-containing superoxide dismutase (SOD1) has peroxidase activity, with H 2 O 2 used as a substrate to oxidize other molecules. We examined peroxidase properties of the extracellular form of SOD (SOD3), a major isoform of SOD in the vessel wall, by using recombinant SOD3 and an in vivo model of atherosclerosis. Methods and Results-In the presence of HCO 3 Ϫ , SOD3 reacted with H 2 O 2 to produce a hydroxyl radical adduct of the spin trap 5-diethoxyphosphoryl-5methyl-1-pyrroline N-oxide (DEMPO). SOD1 and SOD3 were inactivated by H 2 O 2 in a dose-and time-dependent fashion, and this was prevented by physiological levels of uric acid. To examine the in vivo role of uric acid on SOD1 and SOD3, control and apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice were treated with oxonic acid, which inhibits urate metabolism. This treatment increased plasma levels of uric acid in control and ApoE Ϫ/Ϫ mice by Ϸ3-fold. Although increasing uric acid levels did not alter aortic SOD1 and SOD3 protein expression, aortic SOD1 and SOD3 activities were increased by 2-to 3-fold in aortas from ApoE Ϫ/Ϫ mice but not in aortas from control mice. Conclusions-These studies show that SOD1 and SOD3 are partially inactivated in atherosclerotic vessels of ApoE See page 1367Extracellular SOD (SOD3) is also a Cu/Zu-containing SOD that shares Ϸ50% sequence homology with SOD1 within its catalytic region. 7 Compared with the x-ray crystallography structure data for SOD1, 8 all ligands to the copper and zinc atoms can be identified in SOD3, as can the cysteines forming the intramolecular disulfide bond. 7 Thus, these findings suggest that the conformation of the active copper-binding site of SOD3 may resemble the active site of SOD1. The rate constants for dismutation of O 2 ⅐Ϫ by SOD1 and SOD3 are similar, and both enzymes are inhibited by cyanide, azide, and diethyldithiocarbamate. 9 Because SOD3 constitutes 30% to 50% of the total SOD in vascular tissues 10 and is localized in the extracellular space, it would be of considerable importance to determine whether SOD3 also has peroxidase activity and to determine which small molecule reductants can preserve its dismutase activity.Although peroxidase properties of SOD1 have been studied extensively in vitro, evidence is lacking to prove that either SOD1 or SOD3 activities are affected by H 2 O 2 in vivo. In the present study, we sought to determine whether SOD3 has peroxidase activities that are similar to those of SOD1 and to examine small molecules that might prevent the inactivation of SOD3 by using recombinant SOD3 expressed in Pichia pastoris. In these experiments, we found that physiological levels of uric acid completely prevented the inactivation of SOD1 and SOD3 by H 2 O 2 . In additional experiments, we provide evidence for peroxidase activity of SOD1 and SOD3 in vivo, by showing that these enzymes seem to be partially inactivated in the aortas of apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice and that the activity of these

The effect of irbesartan on each inflammatory marker is significant. Our results show that use of irbesartan may retard the inflammatory process seen in premature forms of atherosclerosis.

Abstract-The mechanism(s) by which exercise reduces atherogenic risk remains unknown. This study tested the hypothesis that sustained exercise-induced oxidative stress may increase antioxidant defense in the arterial wall. Acute exercise induced an increase in antibodies to oxidatively modified proteins and catalase in the aortic walls of normal mice compared with sedentary control mice. In male atherogenic diet-fed low density lipoprotein (LDL) receptordeficient mice, exercise lowered plasma cholesterol (15%) and decreased atherosclerotic lesions by 40% compared with values in sedentary control mice, with a concomitant increase in arterial catalase and endothelial NO synthase. Because these mice lack the LDL receptor, the results indicate that the LDL receptor might not be responsible for the exercise-induced lowering of plasma cholesterol. Vitamin E supplementation to exercising LDL receptor-deficient mice did not reduce atherosclerotic lesion formation significantly as opposed to lesion formation in untreated exercised mice. Moreover, vitamin E counteracted the beneficial effects of exercise by preventing the induction of aortic catalase activity and endothelial NO synthase expression. These results might indicate that although vitamin E might have prevented the exercise-induced oxidative stress, its availability in the artery was insufficient to prevent the atherosclerotic process.These results indicate that exercise-induced plasma oxidative stress could be responsible for the prevention of atherosclerosis by stimulating arterial antioxidant response. Furthermore, vitamin E supplementation could be deleterious in exercisers by inhibiting antioxidant enzyme buildup in the arterial wall. (Arterioscler Thromb Vasc Biol.

We had previously suggested that women with endometriosis have increased oxidative stress in the peritoneal cavity. In order to assess whether antioxidant supplementation would ameliorate endometriosis associated symptoms, we performed a randomized, placebo controlled trial of antioxidant vitamins (Vitamin E and C) in women with pelvic pain and endometriosis. Fifty nine women, ages 19–41 years, with pelvic pain and history of endometriosis and/or infertility were recruited for this study. Patients were randomly assigned to two groups: vitamin E (1200 IU) and vitamin C (1000 mg) combination or placebo, daily for eight weeks before surgery. Pain scales were administered at baseline and bi-weekly. Inflammatory markers were measured in the peritoneal fluid obtained from both groups of patients at the end of therapy. Our results indicated that, after treatment with antioxidants, chronic pain (“everyday pain”) improved in 43% of patients in antioxidant treatment group (p=0.0055) as compared to the placebo group. In the same group, dysmenorrhea (“pain associated with menstruation”) and dyspareunia (“pain with sex”) decreased in 37% and 24% patients, respectively. In the placebo group, dysmenorrhea associated pain decreased in 4 patients and no change was seen in chronic pain or dyspareunia. There was significant decrease in peritoneal fluid inflammatory markers, RANTES (p≤0.002), interleukin-6 (p≤0.056) and monocyte chemotactic protein-1 (p≤0.016) after antioxidant therapy compared to patients not on antioxidants. In conclusion, results of this clinical trial show that administration of antioxidants reduces chronic pelvic pain in women with endometriosis and inflammatory markers in the peritoneal fluid.