Oxidative DNA damage and repair in experimental atherosclerosis are reversed by dietary lipid lowering

Increased oxidative stress is a major characteristic of hypercholesterolemi a-induced atherosclerosis. The oxidative environment is mainly created by t he production of reactive oxygen species, which are assumed to mediate vasc ular tissue injury. Oxidative DNA damage resulting from free radical attack remains, however, a poorly examined field in atherosclerosis. Male New Zea land White rabbits were fed a cholesterol-rich diet (0.3%) for 24 weeks. Th e induced atherosclerotic plaques showed elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine (8-oxoG) as demonstrated by immunohistochem istry. 8-oxoG immunoreactivity was found predominantly in the superficial l ayer of the plaque containing numerous macrophage-derived foam cells but no t in the media or in arteries of age-matched control animals. Alkaline sing le-cell gel electrophoresis revealed that the number of DNA strand breaks w as significantly higher in the plaque as compared with control samples of n ormolipemic animals. These changes were associated with the upregulation of DNA repair enzymes (poly[ADP-ribose] polymerase-1, p53, phospho-p53 [phosp horylated at Ser392], and XRCC1 [x-ray repair cross-complementing 1]). DNA strand breaks normalized after 4 weeks of dietary lipid lowering. However, a significant reduction of 8-oxoG immunoreactivity was only observed after a prolonged period of lipid lowering (12 to 24 weeks). Repair pathways star ted to decline progressively when cholesterol-fed animals were placed on a normal diet. In conclusion, oxidative DNA damage and increased levels of DN A repair, both associated with diet-induced hypercholesterolemia, are stron gly reduced during dietary lipid lowering. These findings may provide a bet ter insight into the benefits of lipid-lowering therapy on plaque stabiliza tion.