DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome.

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.

Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells.

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.

DNA damage, p53, apoptosis and vascular disease.

Atherosclerosis is the commonest cause of death in the Western world. The atherosclerotic plaque shows evidence of DNA damage, activation of damage repair pathways, p53 expression and apoptosis, involving a variety of different cell types. This review summarises the evidence for DNA damage in atherosclerosis, the likely stimuli inducing damage, and the increasing role of p53 in mediating apoptosis and its consequences in atherosclerosis.

DNA damage and repair in atherosclerosis.

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.