Review Article

Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications

Figure 2

Mechanisms of hyperglycemia-induced endothelial dysfunction. Key processes responsible for hyperglycemia-induced endothelial dysfunction include the polyol pathway, reactive oxygen species (ROS) formation, and advanced glycation endproducts (AGEs) formation. The excess glucose in endothelial cells enters polyol pathway; the electron donors like reduced nicotinamide adenine dinucleotide (NADH) and Flavin adenine dinucleotide (FADH2) accumulate in the mitochondria, thus affecting the electron transport chain; the excess electrons increase ROS in mitochondria; ROS triggers accumulation of AGEs; ROS and AGEs create mitochondrial DNA damage and mitochondrial dysfunction; protein kinase C (PKC) and AGE mediated activation of nuclear factor kappa B (NFκB) activate the expression of inflammation proteins, tumor suppressor p53, and inducible nitric oxide synthase (iNOS); increased nitric oxide (NO) by iNOS is highly reactive with superoxide anions; the peroxynitrite thus generated acts as a strong oxidant and completes the vicious cycle of oxidative stress by increasing ROS production; accumulation of AGEs also increases ROS production independent of glucose levels.