Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase

Oxygen- and nitrogen-derived free radicals and oxidants play an important r ole in the pathogenesis of diabetic endothelial dysfunction. Recently we pr oposed the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenes is of diabetic endothelial dysfunction. In this study, we tested whether es tablished diabetic endothelial dysfunction is reversible by PARP inhibition . The novel PARP inhibitor PJ34 (10 mg/kg per day PO) was given at various lengths (4 weeks or 3 days) for established streptozotocin-diabetic animals . In addition, we also tested whether incubation of the aortic rings with P J34 (3 mu mol/L) or a variety of other PARP inhibitors for 1 hour affects t he diabetic vascular changes. Both 4-week and 3-day PARP-inhibitor treatmen t of streptozotocin-diabetic mice with established endothelial dysfunction fully reversed the acetylcholine-induced endothelium-dependent relaxations in vitro. Furthermore, 1-hour in vitro incubation of aortae from streptozot ocin-diabetic mice with various PARP inhibitors was able to reverse the end othelial dysfunction. ATP, NAD(+), and NADPH levels were markedly reduced i n diabetic animals, and PARP-inhibitor treatment was able to restore these alterations. Unexpectedly, pharmacological inhibition of PARP not only prev ents the development of the endothelial dysfunction but is also able to rap idly reverse it. Thus, PARP activation and the associated metabolic comprom ise represent an ongoing process in diabetic blood vessels. Pharmacological inhibition of this process is able to reverse diabetic endothelial dysfunc tion.