Does oxidative DNA damage cause atherosclerosis and metabolic syndrome?: new insights into which came first: the chicken or the egg.

See related article, pages 1021–1031 The study of Mercer et al,1 published in this issue of Circulation Research , reports new evidence linking oxidative DNA damage, atherosclerosis, and the metabolic syndrome. Although these relationships have been long proposed,2,–,4 many have criticized previous reports asking the rhetorical question: Which came first, the chicken or the egg? Another question, more specific to the topic of the study by Mercer et al, is: Does oxidative DNA damage actively promote atherosclerosis (and/or metabolic syndrome), or is DNA damage a result of these abnormalities? Conceptually, the theory is attractive. DNA damage occurs often. Every time you walk outside from your office or laboratory to another building, your skin is bombarded by UV irradiation. Were it not for the presence of robust and often redundant DNA repair systems, multiple layers of cells in your skin would be damaged. In some cases, the cells apoptose. The causation between induced DNA damage and cellular apoptosis has been established for many different types of cells.5 In other cases, genomic DNA might be altered in such a way as to promote malignant transformation, or mitochondrial DNA (mtDNA) could be damaged such that the cellular burden of reactive oxygen species (ROS) results in further oxidative DNA damage to nuclear DNA (nDNA).6,7 Why does the same paradigm not fit for oxidative DNA damage as a cause of atherosclerosis? First and foremost, the vasculature is not the skin, and the connection between ROS and oxidative DNA damage (much less the connection to atherosclerosis and metabolic syndrome) is less straightforward to study than the effect of UV irradiation on keratinocytes and melanocytes. Directly measuring the impact of ROS in the vasculature, or on the function of organs responsible for the cluster …