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...

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