Mitochondrial DNA Damage, Oxidative Stress, and Atherosclerosis

Atherosclerosis is an insidious disease that can remain undetected for decades before manifesting, sometimes lethally, in the form of a stroke or myocardial infarction. With >900 000 Americans experiencing a heart attack annually,1 there is a strong need to develop better treatments or preventative measures, but these will necessitate a better understanding of the underlying process. Most evidence suggests that atherosclerosis is initiated by chronic endothelial injury in response to the accumulation of low-density lipoprotein and oxidized low-density lipoprotein in the vessel wall, which stimulates an inflammatory response.2 Although the involvement of elevated circulating lipids and oxidative stress are well recognized in this process (Figure), critical questions remain. These include the question of what causes the atherosclerotic plaque to worsen progressively rather than to resolve, and what causes relatively innocuous, stable plaques to transform into unstable, vulnerable plaques, which are liable to rupture and lead to thrombus formation.Figure. A diagram of the progressive changes ( top to bottom ) during atherosclerosis, detailed in text. ATP indicates adenosine triphosphate; LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; and VSMC, vascular smooth muscle cell.Article see p 702The major risk factors for atherosclerosis include systemic hypertension, elevated plasma lipids, smoking, diabetes mellitus, and aging. Many of these have been shown to damage mitochondria, leading to the proposal that mitochondrial injury is involved in plaque development.2 Mitochondria are important organelles that generate ATP, but they also produce superoxide, a highly reactive oxygen radical, as a by-product, which is rapidly dismuted to hydrogen peroxide. Such reactive oxygen species (ROS), can damage cellular proteins, membranes, and DNA. Whereas genomic DNA is relatively well insulated in the nucleus and is protected by histones, mitochondrial DNA (mtDNA), which encodes several essential proteins of the mitochondrial electron transport chain, is susceptible to oxidative damage. This suggests mitochondrial ROS …