Diabetic vascular damage

Hyperglycemia is important in the pathogenesis of diabetic vascular disease, and the four major molecular mechanisms implicated in hyperglycemia-induced vascular damage reflect a single process: overproduction of superoxide by the mitochondrial electron transport chain. However, the precise pathway by which overproduction of superoxide induces vascular damage has been unclear. In the October 1 Journal of Clinical Investigation, Xueliang Du and colleagues at the Albert Einstein College of Medicine, show that inhibition of GAPDH activity by poly(ADP-ribose) polymerase (PARP) activates three major pathways of hyperglycemic damage in endothelial cells (Journal of Clinical Investigation, 112:1049–1057, October 1, 2003).

Du et al. performed in vitro experiments on bovine aortic endothelial cells and observed that hyperglycemia-induced GAPDH inhibition was a consequence of poly(ADP-ribosyl)ation of GAPDH by PARP—activated by DNA strand breaks produced by mitochondrial superoxide overproduction. In addition, the authors showed that blocking PARP activity with the competitive PARP inhibitors PJ34 or INO-1001 inhibited ...