Cells exposed to high glucose (HG) levels overexpress NF-κB due to histone modifications of the NF-κB promoter by the enzyme Set7.
Diabetes is a major cause of heart attack and stroke—events that are triggered by atherosclerotic plaques and inflammation in the arteries. In diabetic patients who have had extended periods of high blood glucose levels, arterial damage persists long after insulin therapy reduces their mean glucose levels. The authors now provide a molecular explanation for this phenomenon.
The group found that short-lived sugar highs, which occur even in insulin-treated diabetics, trigger histone modifications—an established effect of long-lasting sugar highs. Persistently high sugar levels are known to create reactive oxygen species that induce the generation of methylglyoxal—an activator of the histone methylating enzyme Set7. The authors found that brief blood sugar peaks also activated Set7, which bound to the promoter of the gene for NF-κB, thereby increasing its expression. NF-κB then switched on genes for proteins that help recruit and attach plaque-forming monocytes to vessel walls. These gene expression changes, which were seen in both human heart endothelial cells and mouse aortas, persisted for at least six days after glucose levels returned to normal. These changes were prevented by blocking methylglyoxal production.
Current treatments for diabetes are aimed at reducing mean glucose levels in patients but not the temporary rises in blood sugar levels that occur between insulin injections. This study suggests that adjusting the timing of the treatment regimen to avoid these spikes might be more effective in reducing the risk of heart disease. HB
