Oxidative DNA damage and cardiovascular disease

Reactive oxygen species can directly cause covalent modifications to DNA. Alternatively, they can initiate the formation of lipid hydroperoxides, which undergo homolytic decomposition to the α,β-unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal through two quite separate pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide. The other pathway involves the intermediate formation of 4-hydroperoxy-2-nonenal. Lipid hydroperoxides can also be derived from the action of lipoxygenases and cyclooxygenases on polyunsaturated fatty acids. 4,5-Epoxy-2(E)-decenal forms etheno-2′-deoxyadenosine adduct with DNA, a mutagenic lesion observed in human tissue DNA samples. Several new ethano- and etheno-DNA adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. Malondialdehyde, another genotoxic bifunctional electrophile, forms a propano adduct with 2′-deoxyguanosine (M₁G-dR) rather than an etheno adduct. Very little is known about the consequences of lipid hydroperoxide-mediated DNA damage in cardiovascular diseases. This should prove to be an important area for future research.