Credit: S. Bradbrook/Macmillan Publishers Limited

DNA repair mechanisms offer potential therapeutic targets for atherosclerosis, according to the results of a study published in Circulation. “We find that human plaque vascular smooth muscle cells (VSMCs) show defective repair of oxidative DNA damage, owing to reduced activity and increased degradation of the major base excision repair (BER) enzyme, 8-oxoguanine DNA glycosylase (OGG1),” asserts Martin Bennett, corresponding author of the study.

The researchers also showed that correcting levels of this enzyme in mouse VMSCs not only rescued this defect in BER (which normalized 8-oxoguanine levels) but also markedly reduced atherosclerosis. “This result,” Bennett continues, “demonstrates that levels of oxidative DNA damage that actually occur in atherosclerosis directly promote atherogenesis.”

Previous studies had linked 8-oxoguanine accumulation (a marker of oxidative stress) in VSMCs, macrophages, and endothelial cells to atherosclerosis, but the present study is the first to show that VSMCs from human atherosclerotic plaques have decreased protein levels and enzyme activity of OGG1, and that this defect not only impairs BER and drives 8-oxoguanine accumulation, but also promotes atherosclerosis.

In particular, the researchers showed that the stability and activity of OGG1 are regulated by acetylation at Lys338 and Lys341, and identified p300 acetyltransferase and sirtuin 1 deacetylase as important for regulating BER efficiency in VSMCs. Specifically, p300 levels are reduced by oxidative stress and are also decreased in plaque VSMCs; these reduced p300 levels lead to decreased formation of the p300–OGG1 complex, which both reduces OGG1 enzyme activity and promotes its proteasomal degradation. Reactive oxygen species can also directly reduce OGG1 activity. The resulting decreased efficiency of BER drives 8-oxoguanine accumulation.

In mice, the researchers showed that targeted deletion or knockdown of Ogg1 led to accumulation of 8-oxoguanine as well as increased cell death, senescence, and expression of inflammasome components, which are all proatherogenic. By contrast, overexpression of Ogg1 reduced these responses to oxidative stress and attenuated the development of atherosclerosis.

Thus, the researchers posit, the detrimental effect of chronic oxidative stress on atherosclerosis involves a vicious cycle of oxidative DNA damage, decreased efficiency of BER, and downregulation of OGG1.

atherosclerosis involves a vicious cycle of oxidative DNA damage, decreased … BER, and downregulation of OGG1

In their published report, the researchers suggest that approaches that protect against oxidative DNA damage or promote DNA repair mechanisms could offer benefits in patients with coronary artery disease that go beyond the reduction of traditional cardiovascular risk factors, such as hypercholesterolaemia, diabetes mellitus, and smoking.