Abstract

Poly(ADP ribose) polymerase (PARP) is an abundant nuclear enzyme of eukaryotic cells, which has been implicated in response to DNA injury. Free radical and oxidant induced cell injury can involve the activation of PARP. PARP, when activated by DNA single-strand breaks, initiates an energy consuming cycle by transferring ADP ribose units from NAD to nuclear proteins. The results of this process is a rapid depletion of the intracellular NAD and ATP pools which slows the rate of glycolysis and mitochondrial respiration leading to cellular dysfunction. Recent studies from our group demonstrated the importance of PARP pathway for the pathogenesis of diabetic macrovascular dysfunction, retinopathy and cardiomyopathy. Here we overview our recent progress in the field, which includes (1) delineation of novel molecular mechanisms of the PARP-mediated cellular dysfunction in diabetes, including the link between PARP and pro-inflammatory mediator expression and a link between PARP activation and GAPDH activity suppression; (2) regulation of inflammatory mediator expression by PARP in response to oscillating glucose conditions; (3) recent evidence for PARP activation in tissue specimens of human diabetic patients and (4) recent evidence showing PARP activation in various rodent models of neuropathy, as well as demonstration of the prevention or restoration of the suppression of nerve blood flow and conduction deficit by pharmacological PARP inhibition as well as by genetic PARP deficiency. Overall, PARP emerges as an important novel potential drug target for the correction of various forms of diabetic complications. References: 1.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429 2.Soriano FG, Virág L, Jagtap P et al: Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nature Medicine, 2001; 7: 108-113 3.Pacher P, Liaudet L, Soriano FG et al: The role of poly(ADP-ribose) polymerase in the development of myocardial and endothelial dysfunction in diabetes mellitus. Diabetes, 2002; 51: 514-521

Keywords: vascular dysfunction, endothelium-dependent relaxation, Hyperglycemia, peroxynitrite