Poly-ADP-Ribose-Polymerase Inhibition Ameliorates Hind Limb Ischemia Reperfusion Injury in a Murine Model of Type 2 Diabetes

Abstract

Introduction Diabetes is known to increase poly-ADP-ribose-polymerase (PARP) activity and posttranslational poly-ADP-ribosylation of several regulatory proteins involved in inflammation and energy metabolism. These experiments test the hypothesis that PARP inhibition will modulate hind limb ischemia reperfusion (IR) in a mouse model of type-II diabetes; ameliorate the ribosylation and the activity/transnuclear localization of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Methods db/db mice underwent 1.5hrs of hind limb ischemia followed by 1, 7, or 24hrs reperfusion. The treatment group received the PARP inhibitor PJ34 (PJ34) over a 24hrs period; the untreated group received Lactated ringer’s (LR) at the same time points. IR muscles were analyzed for indices of PARP activity, fiber injury, metabolic activity, inflammation, GAPDH activity /intracellular localization and poly-ADP-ribosylation of GAPDH. Results PARP activity was significantly lower in the PJ34 treated groups compared to the LR group at 7 and 24 hours reperfusion. There was significantly less muscle fiber injury in the PJ34 treated group compared to LR treated mice at 24 hrs reperfusion. PJ34 lowered levels of select proinflammatory molecules at 7hrs and 24hrs IR. There were significant increases in metabolic activity only at 24 hours IR in the PJ34 group, which temporally correlated with increase in GAPDH activity, decreased GAPDH poly ADP-ribosylation and nuclear translocation of GAPDH. Conclusions PJ34 reduced PARP activity, GAPDH ribosylation, GAPDH translocation, ameliorated muscle fiber injury, and increased metabolic activity following hind limb IR injury in a murine model of type-II diabetes. PARP inhibition might be a therapeutic strategy following IR in diabetic humans.

Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity

“…4 [114][115][116][117]. That over-activation of PARP contributes to the pathogenesis of diabetes has been further supported by evidence that PRAP knockout or deficient animals are protected from chemical-induced diabetes [118][119][120] and that PARP inhibitors prevent development of diabetes and its complications [121][122][123][124][125]. This pathway involves activation of glutamine fructose-6-P amidotransferase that converts fructose 6-P to glucosamine 6-P.…”

Dimethylnitrosamine-Induced Reduction in the Level of Poly-ADP-Ribosylation of Histone Proteins of Blood Lymphocytes - a Sensitive and Reliable Biomarker for Early Detection of Cancer

“…In this work attempts has been made to explore the possibility of poly ADP-ribosylation (PAR) of histone proteins as a biomarker for early detection of cancer. Correlations between the cellular PAR and different cellular and molecular events including carcinogenesis have been observed in our laboratory and elsewhere (Sharan et al, 2005;Devi and Sharan, 2006;Kma and Sharan, 2006;Sala et al, 2008;Binu et al, 2012;Ozaki et al, 2012;Chiou et al, 2013;Donà et al, 2013;Kalmar-Nagy et al, 2013;Long et al, 2013;Yuan et al, 2013). PAR was monitored by ELISA based immuno-probe assay, developed in our laboratory (Sharan et al, 2005).…”

“…A multitude of cellular functions and molecular events, including carcinogenesis, angiogenesis, nucleosome-remodelling, cell death, etc. are known to have strong involvement of PAR (Devi and Sharan 2006;Kma and Sharan, 2006;Sala et al, 2008;Binu et al, 2012;Ozaki et al, 2012;Chiou et al, 2013;Donà et al, 2013;Kalmar-Nagy et al, 2013;Long et al, 2013;Yuan et al, 2013).…”

Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis

“…We selected PARP as our molecule of interest to study because PARP is pathologically overactivated in both diabetic and ischemic conditions. [9][10][11][12][13] The role of PARP in wound healing has been previously explored in the setting of chronic nonhealing wounds due to radiation 14 and in corneal epithelial healing in diabetic rats, 15 in which PARP was found to be overactivated. PARP inhibition proved to be beneficial to wound healing in both of these settings.…”