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I. G. Obrosova, J. Shin, V. R. Drel, W. Xu, J. Zhang, T. Ahmad, A. El-Remessy; Poly(ADP-Ribose)Polymerase Inhibition Counteracts Diabetes-Induced Nitrosative Stress and Apoptosis in Retina and High-Glucose Exposed Cultured Retinal Vascular Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3639.
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To access the role for poly(ADP-ribose) polymerase activation in oxidative stress and apoptosis in diabetic retina and FFA-exposed retinal pericytes and endothelial cells. FFA are an important player in oxidative stress and apoptosis of vascular cells in diabetes.
Control (C) and STZ-diabetic (D) rats were treated with/without the PARP inhibitors, 1,5-isoquinolinediol (ISO, 3 mgkg-1d-1 i.p.) or 10-(4-Methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]-anthracen-3-one (GPI 15427, 30 mgkg-1d-1), for 10 wks after 2 wks without treatment. The rate of apoptosis was assessed in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. Primary bovine retinal pericytes and endothelial cells were cultured with/without 0.6 M palmitate, for 48 h. Apoptosis was assessed by TUNEL and caspase-3 assays, superoxide production by ethidium fluorescence, cell viability with Trypan blue, and nitrotyrosine (NT) and poly(ADP-ribose) (PAR) by immunocytochemistry.
The number of TUNEL-positive nuclei (Mean ± SEM) was increased ~4-fold in D (207 ± 33 vs 49 ± 4 in C, p < 0.01), and this increase was completely corrected in D+ISO and D+GPI 15427 (49 ± 15 and 43 ± 7, respectively, p < 0.01 vs D). Palmitate, at the 0.2-0.8 M concentrations, dose dependently increased superoxide production and reduced cell viability in cultured retinal cells. GPI 15427, 20 microM, prevented FFA-induced increase in the rate of apoptosis, and alleviated NT and PAR accumulation in both pericytes and endothelial cells.
PARP inhibition counteracts oxidative stress and prevents apoptosis in diabetic retina and FFA-exposed retinal pericytes and endothelial cells.
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