Redox regulation of diabetic vascular remodeling by s-glutathiolation

Among the many potential catalysts for the pathophysiological manifestations of diabetes, overproduction of reactive oxygen species (ROS) appears to be a common upstream event. Protein S-glutathiolation, the reversible covalent addition of glutathione to cysteine residues on target proteins, is a candidate mechanism by which changes in intracellular redox state and generation of ROS can modulate protein function. The PI hypothesized that the increased ROS generation in type 2 diabetes promotes protein S-glutathiolation, in turn leading to neointimal hyperplasia, accelerated atherosclerosis, and revascularization failure. He identified two highly glutathiolated proteins, annexin A2 and Beta-actin. These proteins are involved in cellular processes critical to vascular remodeling, such as proliferation and migration. Moreover, recent data suggest that these proteins interact dynamically with one another. Thus, the PI is studying the physiological and cellular effects of S-glutathiolation in type 2 diabetes; identifying the pathways involved in S-glutathiolation-mediated phenotypes; and 3) establishing the role of S-glutathiolation as a therapeutic target to prevent diabetes-induced premature revascularization failure.