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576767 
Journal Article 
Lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions 
Nair, J; De Flora, S; Izzotti, A; Bartsch, H 
2007 
1 
Mutation Research: Fundamental and Molecular Mechanisms of Mutagenesis
ISSN: 0027-5107
EISSN: 1873-135X 
621 
1-2 
95-105 
Atherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N6-ethenodeoxyadenine ([var epsilon]dA) and 3,N4-ethenodeoxycytosine ([var epsilon]dC). By applying an ultrasensitive 32P-postlabeling-immunoaffinity method, [var epsilon]dA and [var epsilon]dC were quantified in abdominal aorta SMCs from 13 atherosclerotic patients and 3 non-smoking subjects without atherosclerotic lesions. The levels of etheno-adducts ranged for [var epsilon]dA from 2.3 to 39.6/108 dA and for [var epsilon]dC from 10.7 to 157.7/108 dC, with a high correlation between [var epsilon]dA and [var epsilon]dC (r = 0.84, P = 0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both [var epsilon]dA (means 15.2 versus 7.3, P = 0.06) and [var epsilon]dC (71.9 versus 51.6, not significant). [var epsilon]dC levels were higher in either ex-smokers (P = 0.03) or smokers (P = 0.07) than in non-smokers. There was a poor correlation between either [var epsilon]dA or [var epsilon]dC and 8-hydroxy-2'-deoxyguanosine, whereas significant positive correlations were detected with the levels of several postlabeled bulky aromatic DNA adducts. In conclusion, two different types of DNA damage may be involved in atherosclerotic plaque formation and progression: (i) bulky aromatic compounds, to which aorta SMCs are chronically exposed in smokers, can either covalently bind to DNA, induce redox-cycling via quinone intermediates and/or activate local chronic inflammatory processes in the arterial wall; ii) this in turn leads to a self perpetuating generation of reactive oxygen species, LPO-products and increasing DNA-damage, as documented by the presence of high levels of miscoding etheno-DNA adducts in human aorta SMCs. 
Human atherosclerotic plaques; Cigarette smoke carcinogenesis; DNA-adduct formation; Inflammation; Atherogenic risk factors