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

被引:154
作者
Martinet, W
Knaapen, MWM
De Meyer, GRY
Herman, AG
Kockx, MM
机构
[1] Univ Antwerp, Div Pharmacol, Wilrijk, Belgium
[2] Cardiovasc Translat Res Inst Middelehim Antwerp, Antwerp, Belgium
关键词
DNA damage; DNA repair; apoptosis; oxidant stress; atherosclerosis;
D O I
10.1161/hh0701.088684
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Increased oxidative stress is a major characteristic of hypercholesterolemia-induced atherosclerosis. The oxidative environment is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage resulting from free radical attack remains, however, a poorly examined field in atherosclerosis. Male New Zealand White rabbits were fed a cholesterol-rich diet (0.3%) for 24 weeks. The induced atherosclerotic plaques showed elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine (8-oxoG) as demonstrated by immunohistochemistry. 8-oxoG immunoreactivity was found predominantly in the superficial layer of the plaque containing numerous macrophage-derived foam cells but not in the media or in arteries of age-matched control animals. Alkaline single-cell gel electrophoresis revealed that the number of DNA strand breaks was significantly higher in the plaque as compared with control samples of normolipemic animals. These changes were associated with the upregulation of DNA repair enzymes (poly[ADP-ribose] polymerase-1, p53, phospho-p53 [phosphorylated 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 started to decline progressively when cholesterol-fed animals were placed on a normal diet. In conclusion, oxidative DNA damage and increased levels of DNA repair, both associated with diet-induced hypercholesterolemia, are strongly reduced during dietary lipid lowering. These findings may provide a better insight into the benefits of lipid-lowering therapy on plaque stabilization.
引用
收藏
页码:733 / 739
页数:7
相关论文
共 38 条
[1]   Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma - A potential mechanism of lesion stabilization [J].
Aikawa, M ;
Rabkin, E ;
Okada, Y ;
Voglic, SJ ;
Clinton, SK ;
Brinckerhoff, CE ;
Sukhova, GK ;
Libby, P .
CIRCULATION, 1998, 97 (24) :2433-2444
[2]   Enhanced phosphorylation of p53 by ATN in response to DNA damage [J].
Banin, S ;
Moyal, L ;
Shieh, SY ;
Taya, Y ;
Anderson, CW ;
Chessa, L ;
Smorodinsky, NI ;
Prives, C ;
Reiss, Y ;
Shiloh, Y ;
Ziv, Y .
SCIENCE, 1998, 281 (5383) :1674-1677
[3]   Oxidative decay of DNA [J].
Beckman, KB ;
Ames, BN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (32) :19633-19636
[4]  
Bennett MR, 1999, BIOCHEM PHARMACOL, V58, P1089
[5]   Nitric oxide-induced deamination of cytosine and guanine in deoxynucleosides and oligonucleotides [J].
Caulfield, JL ;
Wishnok, JS ;
Tannenbaum, SR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) :12689-12695
[6]   Inducible nitric oxide synthase colocalizes with signs of lipid oxidation/peroxidation in human atherosclerotic plaques [J].
Cromheeke, KM ;
Kockx, MM ;
De Meyer, GRY ;
Bosmans, JM ;
Bult, H ;
Beelaerts, WJF ;
Vrints, CJ ;
Herman, AG .
CARDIOVASCULAR RESEARCH, 1999, 43 (03) :744-754
[7]   Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells [J].
Croteau, DL ;
Bohr, VA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (41) :25409-25412
[8]   Evaluation of the in vitro direct and indirect genotoxic effects of cobalt compounds using the alkaline comet assay.: Influence of interdonor and interexperimental variability [J].
De Boeck, M ;
Lison, D ;
Kirsch-Volders, M .
CARCINOGENESIS, 1998, 19 (11) :2021-2029
[9]   NITRIC-OXIDE INDUCES OXIDATIVE DAMAGE IN ADDITION TO DEAMINATION IN MACROPHAGE DNA [J].
DEROJASWALKER, T ;
TAMIR, S ;
JI, H ;
WISHNOK, JS ;
TANNENBAUM, SR .
CHEMICAL RESEARCH IN TOXICOLOGY, 1995, 8 (03) :473-477
[10]   Peroxynitrite mediated oxidation of purine bases of nucleosides and isolated DNA [J].
Douki, T ;
Cadet, J .
FREE RADICAL RESEARCH, 1996, 24 (05) :369-380