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

Abstract

Diabetic patients frequently suffer from retinopathy, nephropathy, neuropathy and accelerated atherosclerosis. The loss of endothelial function precedes these vascular alterations. Here we report that activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of endothelial dysfunction in diabetes. Destruction of islet cells with streptozotocin in mice induced hyperglycemia, intravascular oxidant production, DNA strand breakage, PARP activation and a selective loss of endothelium-dependent vasodilation. Treatment with a novel potent PARP inhibitor, starting after the time of islet destruction, maintained normal vascular responsiveness, despite the persistence of severe hyperglycemia. Endothelial cells incubated in high glucose exhibited production of reactive nitrogen and oxygen species, consequent single-strand DNA breakage, PARP activation and associated metabolic and functional impairment. Basal and high-glucose-induced nuclear factor-kappaB activation were suppressed in the PARP-deficient cells. Our results indicate that PARP may be a novel drug target for the therapy of diabetic endothelial dysfunction.

Hypouricemia linked to an overproduction of nitric oxide is an early marker of oxidative stress in female subjects with type 1 diabetes

“…Hyperglycemia stimulates an overproduction of O 2 − (above all, by mitochondria), which reacts with the NO produced by the constitutional isoform of endothelial nitric oxide synthase (eNOS), thus generating peroxynitrite. The latter compound causes DNA strand breaks that consequently activate poly(ADPribose) polymerase (PARP), which in turn increases the nuclear concentration of nuclear factor kappa B (NF-κB) [26]. Nuclear factor kappa B enhances the transcription of inducible nitric oxide synthase (iNOS) [27] both in endothelial and in smooth muscle cells of the vascular wall, resulting in a further elevation of NO and, obviously, peroxynitrite levels.…”

Diabetes and renal tubular cell apoptosis

“…Several kinases like JNK, p38 [33] and cdc2/cyclin B kinase [34] have been noticed to phosphorylate/inactivate Bcl-2 as a physiological process during normal cell cycle progression or as a defense mechanism following the activation by various stimuli and stress. Phosphorylation/inactivation of Bcl-2 inactivates the antiapoptotic effect, which triggers the release of cytochrome C from the mitochondria leading to the activation of downstream caspases [35][36][37] . Another important protein involved in apoptosis is poly (ADP-Ribose) polymerase (PARP), a DNA repair enzyme that is cleaved by the downstream caspases.…”

Effect of Poly(ADP-Ribose) Polymerase Inhibition on Outer Medullary Hypoxic Damage

“…Finally, the attenuation of renal functional impairment at the absence of a significant morphological tubular protection might reflect improvement of renal hemodynamics, with the PARP inhibitor mitigating vascular endothelial dysfunction [16, 17, 18, 19]. …”

“…PARP activation was found to exacerbate acute and ongoing involutional tissue damage and its inhibition is currently considered a potential novel therapeutic approach in the attenuation of neuronal [6], splanchnic [7, 8]skeletal [9]and cardiac muscle hypoxic cell death [9, 10]. PARP inhibition may also attenuate tissue damage during toxic and physical insults [11, 12]or following an inflammatory reaction [13, 14], and can restore chronically [15, 16, 17, 18]or acutely acquired [14, 19]endothelial dysfunction.…”