Role of histone methyltransferase EZH2 in diabetes associated atherosclerosis

Diabetes can damage blood vessels by accelerating the process of fatty plaque development known as atherosclerosis. The prevalence of atherosclerosis is increasing rapidly worldwide. Atherosclerosis begins with endothelial cells damage ultimately leading to blood vessel blockage. Endothelial cells line the interior surface of blood vessels and are the first type of cells exposed to high blood glucose levels. Endothelial damage in the blood vessels is evident in patients with diabetes. There is no effective treatment to date that would address endothelial injury in this setting. EZH2 is an enzyme that changes chromatin structure to regulate the expression of genes involved in endothelial damage. Several studies have found that EZH2 activity is elevated in high glucose treated endothelial cells. However, whether this over activity of EZH2 damages endothelial cells in diabetes-associated atherosclerosis is not known. Thus, I hypothesize that over-activity of EZH2 mediated by high glucose concentrations and other stressors such as high fat diet is associated with endothelial damage and atherosclerosis. I will address this using pharmacological and genetic approaches in animal model of diabetic atherosclerosis. In the pharmacological approach, I will use a drug that inhibits EZH2 activity and thus may improve endothelial function and protect vessels from plaque development. In the genetic approach, I will generate endothelial specific knockout mice and use streptozotocin to make them diabetic. Aorta and blood will be collected at the end of study for functional, structural and molecular analysis. By directly testing the efficacy of pharmacological inhibition of EZH2, our results may provide evidence for the potential use of chromatin modifying drug in preventing vascular damage caused by high blood glucose concentrations.