Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?
Figure 1
Hyperglycemia-induced oxidative stress and endothelial dysfunction (possible role of ER stress). High glucose levels in circulation can divert glucose into alternative biochemical pathways leading to the increase in advanced glycation end products (AGEs), glucose autooxidation, hexosamine and polyol flux, and activation of classical isoforms of protein kinase C, that are considered to be the mediators of hyperglycemia-induced cellular injury. Many different pathways involved in hyperglycemia-mediated endothelial dysfunction induced by hyperglycemia lead to considerable generation of reactive oxygen species (ROS), which is responsible for the oxidative stress. The excessive ROS so formed can then aggravate cellular injury by promoting activation of the biochemical pathways (red dotted arrows) that initiate ROS generation in the first place as a response to hyperglycemia, thus completing a vicious cycle. Superoxide anion can also react with NO to yield peroxynitrite which is also known to be a mediator of endothelial dysfunction. It is still unclear whether the ER stress response can be initiated as a direct response to the increasing load on protein synthesis and maturation due to hyperglycemia or due to the hyperglycemia-associated oxidative stress. The possibility that ER stress response also can lead to excessive ROS formation cannot be ruled out.
