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

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 of metabolic abnormalities commonly referred to as the metabolic syndrome (liver, pancreas, and adipose tissue), is not possible in the same way in which it is for the skin. The notion that oxidative DNA damage contributes to atherosclerosis and its complications is far from new. In 1992, Wallace was among the first to suggest that mtDNA mutations and/or damage correlate with human disease.8 Since that time, one consistent theme from the many laboratories studying oxidative DNA damage and atherosclerosis has been a focus on mtDNA damage. MtDNA lacks histone protection, and mechanisms for repair of mtDNA damage are far less comprehensive than those that exist for nDNA damage.9 A teleologic argument for this difference is that most cells have multiple mitochondria, and damage to a small percentage of mitochondria is unlikely to adversely affect the cell in any major way. This is probably true, because major phenotypes emerge only when mitochondrial function is dramatically altered. Although a link between mtDNA damage and atherosclerosis has been established since the 1990s,3,8,10 the causality was not proven. Enter Mercer et al,1 who chose to use the ataxia telangiectasia mutated (ATM) protein defect as a model for studying whether oxidative mtDNA damage causes atherosclerosis and the metabolic syndrome. The rationale for these experiments was based on 2 different types of findings. First, some patients with ataxia telangiectasia have insulin resistance and presumably the metabolic syndrome,11 and various studies implicate ATM function in atherosclerosis.12 Secondly, ATM is a serine/threonine kinase that plays a role in DNA repair, mtDNA content, mitochondrial biogenesis, and glucose homeostasis.13,14 For the present study, Mercer et al1 used mice that were apolipoprotein (Apo)E null and either ATM haplodeficient or normal in ATM function. In the ApoE / background, ATM haplodeficiency was associated with hyperlipidemia, hypertension, weight gain, increased numbers of adipocytes, and inflammatory changes in the liver, as well as other features consistent with the metabolic syndrome. These mice also displayed mtDNA damage and mitochondrial dysfunction in multiple organs. An initial impression is that this study hardly overcomes the burden of proof of causality between oxidative DNA damage and the metabolic syndrome and atherosclerosis. Indeed, a significant limitation of the present study is that the authors did not address mtDNA damage and mitochondrial dysfunction in the aortas from ApoE / /ATM / mice. These studies could have provided additional insight into the relative roles of nDNA and mtDNA damage in vascular dysfunction. However, in the breadth of their studies, the authors do, in our opinion, provide a level of evidence consistent with mtDNA damage causing the metabolic syndrome and atherosclerosis, well surpassing that of prior studies. The authors were able to define a complex phenotype consisting of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology (N.R.M., R.-H.Z., A.E.V., X-L.N., M.S.R.), Department of Medicine (N.R.M., A.E.V., X-L.N., M.S.R.), and McAllister Heart Institute (R.-H.Z., M.S.R)., University of North Carolina at Chapel Hill. Correspondence to Marschall S. Runge, Department of Medicine, 125 MacNaider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7005. E-mail [email protected] (Circ Res. 2010;107:940-942.) © 2010 American Heart Association, Inc.