Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation

Diabetic patients frequently suffer from retinopathy, nephropathy, neuropat hy and accelerated atherosclerosis. The loss of endothelial function preced es these vascular alterations. Here we report that activation of poly(ADP-r ibose) polymerase (PARP) is an important factor in the pathogenesis of endo thelial dysfunction in diabetes. Destruction of islet cells with streptozot ocin in mice induced hyperglycemia, intravascular oxidant production, DNA s trand breakage, PARP activation and a selective loss of endothelium-depende nt vasodilation. Treatment with a novel potent PARP inhibitor, starting aft er the time of islet destruction, maintained normal vascular responsiveness , despite the persistence of severe hyperglycemia. Endothelial cells incuba ted in high glucose exhibited production of reactive nitrogen and oxygen sp ecies, consequent single-strand DNA breakage, PARP activation and associate d metabolic and functional Impairment. Basal and high-glucose-induced nucle ar factor-kappaB activation were suppressed in the PARP-deficient cells. Ou r results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.