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,N-6-ethenodeoxyadenine (epsilon dA) and 3,N-4-ethenodeoxycytosine (epsilon dC). By applying an ultrasensitive P-32-postlabeling-immunoaffinity method, epsilon dA and 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 epsilon dA from 2.3 to 39.6/10(8) dA and for epsilon dC from 10.7 to 157.7/10(8) dC, with a high correlation between epsilon dA and epsilon dC (r=0.84, P=0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both epsilon dA (means 15.2 versus 7.3, P=0.06) and epsilon dC (71.9 versus 51.6, not significant). 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 epsilon dA or 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. (C) 2007 Elsevier B.V. All rights reserved.
