Suppression of Oxidative Stress as a Mechanism of Reduction of Hypercholesterolemic Atherosclerosis by Cyclooxygenase Inhibitors

Abstract

Hypercholesterolemia increases the formation of arachidonic acid from membrane phospholipids. Reactive oxgyen species (ROS) are generated during the synthesis of prostaglandins (PGs) from arachidonic acid. ROS have been implicated in the development of hypercholesterolemic atherosclerosis. Inhibition of the synthesis of PGs by indomethacin or naproxen, therefore, should be able to prevent the generation of ROS and hence the development of atherosclerosis. The objective of this study was to determine if indomethacin or naproxen reduces the development of hypercholesterolemic atherosclerosis and if this reduction is associated with decrease in the oxidative stress. Rabbits were assigned to 5 groups: Group I, control; Group II, indomethacin control (6 mg·kg body wt⁻¹·d⁻¹ PO); Group III, 0.5% cholesterol; Group IV, 0.5% cholesterol plus indomethacin (6 mg·kg body wt⁻¹·d⁻¹ PO); Group V, 0.5% cholesterol plus naproxen (10 mg·kg body wt⁻¹·d⁻¹ PO). Blood samples were collected before (time 0) and after 1 and 2 months of experimental diets for measurement of serum triglycerides (TG), total cholesterol (TC), LDL and HDL cholesterol (LDL-C, HDL-C), serum malondialdehyde (MDA), and white blood cell chemiluminescence (WBC-CL), a measure of ROS produced by WBC. At the end of the protocol, the aorta was removed for measurement of atherosclerotic plaques, MDA, an aortic tissue lipid peroxidation product, and aortic tissue chemiluminescence (Aortic-CL), a marker of antioxidant reserve. Serum TG, LDL-C, HDL-C and the ratio TC/HDL-C increased to a similar extent in Groups III, IV and V at months 1 and 2 compared with time 0. Indomethacin and naproxen had practically no effect on serum lipid levels. Serum MDA increased to a similar extent in Groups III and IV and to a greater extent in Group V compared with 0 time. WBC-CL activity was similar in the 5 groups. There was an increase in the levels of aortic-MDA in Groups III and IV as compared to Group I or II, the increase being smaller in Group IV than in Group III. Aortic MDA values in Group V were lower than those in all other groups. Antioxidant reserve increased in Groups III and V but remained unchanged in Group IV compared to Groups I or II. Indomethacin and naproxen reduced hypercholesterolemic atherosclerosis by 46.73% and 46.56%, respectively. Indomethacin and naproxen, the inhibitors of prostaglandin synthesis, reduced hypercholesterolemic atherosclerosis and this effect was associated with a decrease in the oxidative stress. These results suggest that ROS generated during synthesis of prostaglandins in hypercholesterolemia might in part contribute to the development of hypercholesterolemic atherosclerosis.