Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly (ADP-ribose) polymerase activation

Peroxynitrite and hydroxyl radicals are potent initiators of DNA single-str and breakage, which is an obligatory stimulus for the activation of the nuc lear enzyme poly(ADP ribose) polymerase (PARP). In response to high glucose incubation medium in vitro, or diabetes and hyperglycemia in vivo, reactiv e nitrogen and oxygen species generation occurs. These reactive species tri gger DNA single-strand breakage, which induces rapid activation of PARP. PA RP in turn depletes the intracellular concentration of its substrate, NAD(), slowing the rate of glycolysis, electron transport, and ATP formation. T his process results in acute endothelial dysfunction in diabetic blood vess els. Accordingly, inhibitors of PARP protect against endothelial injury und er these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also appears to modulate the course of inflammation by regulating the activation of nuclear factor kappaB, and the expression of a number of genes, including the gene for intercellular adhesion molecule I and the inducible nitric oxide synthase. The research i nto the role of PARP in diabetic vascular injury is now supported by novel tools, such as new classes of potent inhibitors of PAR-P and genetically en gineered animals lacking the gene for PARR Pharmacological inhibition of PA RP emerges as a potential approach for the experimental therapy of diabetic vascular dysfunction.