Rationale: DNA damage is present in both genomic and mitochondrial DNA in atherosclerosis. However, whether DNA damage itself promotes atherosclerosis, or is simply a byproduct of the risk factors that promote atherosclerosis, is unknown. Objective:To examine the effect of DNA damage on atherosclerosis, we studied apolipoprotein (Apo)E ؊/؊ mice that were haploinsufficient for the protein kinase ATM (ataxia telangiectasia mutated), which coordinates DNA repair. Methods and Results: ATM

Abstract-Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used in atherosclerosis to reduce serum cholesterol, statins have multiple other effects, including direct effects on cells of the vessel wall. Recently, DNA damage, including telomere shortening, has been identified in vascular smooth muscle cells (VSMCs) in human atherosclerosis. Although statins reduce DNA damage in vitro, the mechanisms by which they might protect DNA integrity in VSMCs are unknown. We show that human atherosclerotic plaque VSMCs exhibit increased levels of double-stranded DNA breaks and basal activation of DNA repair pathways involving ataxia telangiectasia-mutated (ATM) and the histone H2AX in vivo and in vitro. Oxidant stress induced DNA damage and activated DNA repair pathways in VSMCs. Statin treatment did not reduce oxidant stress or DNA damage but markedly accelerated DNA repair. Accelerated DNA repair required both the Nijmegen breakage syndrome (NBS)-1 protein and the human double minute protein Hdm2, accompanied by phosphorylation of Hdm2, dissociation of NBS-1 and Hdm2, inhibition of NBS-1 degradation, and accelerated phosphorylation of ATM. Statin treatment reduced VSMC senescence and telomere attrition in culture, accelerated DNA repair and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR (ATM and Rad3-related) activity in atherosclerosis. We conclude that statins activate a novel mechanism of accelerating DNA repair, dependent on NBS-1 stabilization and Hdm2. Statin treatment may delay cell senescence and promote DNA repair in atherosclerosis. H uman atherosclerotic plaques demonstrate evidence of DNA damage, including expression of oxidized guanosine residues, DNA strand breaks, and activation of DNA repair enzymes. 1,2 Although DNA damage is seen in both vascular smooth muscle cells (VSMCs) and macrophages, the mechanisms underlying DNA damage and its biological consequences are unknown. For example, DNA damage can promote apoptosis and premature cell senescence (reviewed elsewhere 3 ), both of which are prominent in VSMCs in human atherosclerosis. 2,4 Conversely, accelerating DNA repair may prevent or reduce accumulated DNA damage, preventing apoptosis or cell senescence.DNA damage induces a cascade of activated proteins that act as sensors and effectors of the damage response, to stall the cell cycle allowing repair to occur, to promote repair, or to induce apoptosis if damage is severe. DNA damage activates Nijmegen breakage syndrome (NBS)-1, a ubiquitously expressed 754-aa protein and key regulator of the MRE11/RAD-50/NBS-1 (MRN) complex. 5,6 MRN promotes early processing of double-strand breaks (DSBs) via DNA binding and nuclease activities, functions as a DSB sensor, and also recruits the ataxia telangiectasia-mutated (ATM) protein to DSBs, followed by ATM activation. 7-9 ATM is normally present as inactive dimers, but DSB exposure induces autophosphorylation at Ser1981, dimer dissociation, and kinase activation. ATM has multiple downstream substrates that me...

There is increasing evidence that human atherosclerosis is associated with damage to the DNA of both circulating cells, and cells of the vessel wall. Reactive oxygen species are the most likely agents inducing DNA damage in atherosclerosis. DNA damage produces a variety of responses, including cell senescence, apoptosis and DNA repair. This review summarises the evidence for DNA damage in atherosclerosis, the cellular responses to damage and the mechanisms of signalling DNA damage.

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