Lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions

Jagadeesan Nair, Silvio De Flora, Alberto Izzotti, Helmut Bartsch

Research output: Contribution to journalArticlepeer-review

Abstract

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 (εdA) and 3,N4-ethenodeoxycytosine (εdC). By applying an ultrasensitive 32P-postlabeling-immunoaffinity method, εdA and εdC 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 εdA from 2.3 to 39.6/108 dA and for εdC from 10.7 to 157.7/108 dC, with a high correlation between εdA and εdC (r = 0.84, P = 0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both εdA (means 15.2 versus 7.3, P = 0.06) and εdC (71.9 versus 51.6, not significant). εdC 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 εdA or εdC 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.

Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume621
Issue number1-2
DOIs
Publication statusPublished - Aug 1 2007

Keywords

  • Atherogenic risk factors
  • Cigarette smoke carcinogenesis
  • DNA-adduct formation
  • Human atherosclerotic plaques
  • Inflammation

ASJC Scopus subject areas

  • Molecular Biology
  • Health, Toxicology and Mutagenesis

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