Decreased levels of lipid peroxidation-induced DNA damage in the onset of atherogenesis in apolipoprotein E deficient mice.
Increased oxidative stress and subsequent lipid peroxidation (LPO) are thought to be critical events in the formation of atherosclerotic lesions in apolipoprotein E deficient mice (ApoE-KO). LPO derived reactive aldehydes react with DNA to form exocyclic etheno-DNA adducts. These pro-mutagenic DNA lesions are known to be involved in the initiation of carcinogenesis, but their role in the development of atherosclerosis is unknown. In the present study we show that levels of the LPO derived 1,N(6)-ethenodeoxyadenosine (varepsilondA) and 3,N(4)-ethenodeoxycytidine (varepsilondC) were both significantly lower in aorta of 12 weeks old ApoE-KO mice as compared to their wild type controls (1.6+/-0.3 versus 3.2+/-0.8 varepsilondA per 10(8) parent nucleotides, P=0.04 and 4.8+/-0.8 versus 9.2+/-2.1 for varepsilondC, P=0.02). Moreover, levels of both DNA adduct types were inversely related with total plasma cholesterol levels. Consequently, lowest etheno-DNA adduct levels were observed in ApoE-KO mice on a high fat diet. Hypercholesterolemia has previously been associated with increased expression of base excision repair (BER) enzymes, which could explain the lower levels of etheno-DNA adducts in ApoE-KO mice as compared to wild type controls. Indeed, increased staining for the BER-specific DNA repair enzyme apurinic/apyrimidinic endonuclease (Ape1/Ref1) was observed by immunohistochemistry in the endothelium and the first layers of arterial smooth muscle cells of ApoE-KO mice as compared to their wild type counterparts. A high fat diet further increased overall Ape1/Ref1 protein expression in ApoE-KO mice. Although these data suggest no role for increased LPO derived DNA damage in the onset of atherogenesis in ApoE-KO mice, the potentially modulating role of Ape1/Ref1 in the arterial wall deserves further attention.
Godschalk
Roger W L
RW
German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Albrecht
Catrin
C
Curfs
Danielle M J
DM
Schins
Roel P F
RP
Bartsch
Helmut
H
van Schooten
Frederik-Jan
FJ
Nair
Jagadeesan
J
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics
D001057:Apolipoproteins E; D018736:DNA Adducts; D008055:Lipids; D045643:DNA Repair Enzymes