Different responses of fluvastatin to cholesterol-induced oxidative modifications in rabbits: evidence for preventive effect against DNA damage.
Hypercholesterolemia is a major risk factor for atherosclerosis and related occlusive vascular diseases. We investigated the effect of low-dose fluvastatin (2 mg kg(-1) day(-1)) on antioxidant enzyme activities [superoxide dismutase (SOD), catalase], vascular reactivity changes and oxidatively induced DNA damage in early stage of atherosclerosis in hypercholesterolemic rabbits. The animals were divided into three groups each composed of 10 rabbits. The control group received a regular rabbit chow diet, and the cholesterol group had hypercholesterolemic diet (2%, 4 weeks). The fluvastatin group was given hypercholesterolemic diet plus fluvastatin. Dietary intake of cholesterol significantly increased total cholesterol levels in rabbits (control, 0.85 ± 0.29; cholesterol, 12.04 ± 4.61; fluvastatin, 8.07 ± 2.72 mmol l(-1)). Hypercholesterolemic diet revealed discernible fatty streaks in arcus aortae. Fluvastatin significantly reduced the areas of the lesions. The diet significantly increased SOD activities in both erythrocyte and tissue. Treatment with fluvastatin normalized the increased activity of SOD in both erythrocyte and aortic tissues from the cholesterol group. Cholesterol feeding decreased the sensitivity to acetylcholine, and treatment with fluvastatin significantly restored the diminished sensitivity to acetylcholine in thoracic aortae. Cholesterol feeding caused oxidatively induced DNA damage in liver tissues determined by the increased levels of 8-hydroxyguanine (8-OH-Gua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua). Fluvastatin decreased only FapyGua level in liver. In conclusion, our results may suggest that fluvastatin seems to play a protective role on high cholesterol-induced oxidative stress and DNA damage.
Department of Pharmacology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey. gulnur.sevin@ege.edu.tr
Gulnur
G
Sevin
Mukadder
M
Yasa
Delen Yasemin
DY
Akcay
Guldal
G
Kirkali
Zeliha
Z
Kerry
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000378:metabolism
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D002784:Cholesterol; D013482:Superoxide Dismutase