Obrosova Irina G, Drel Viktor R, Pacher Pal, Ilnytska Olga, Wang Zhong Q, Stevens Martin J, Yorek Mark A
Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Rd., Baton Rouge, Louisiana 70808, USA.
Diabetes. 2005 Dec;54(12):3435-41. doi: 10.2337/diabetes.54.12.3435.
Poly(ADP-ribose) polymerase (PARP) activation, an important factor in the pathogenesis of diabetes complications, is considered a downstream effector of oxidative-nitrosative stress. However, some recent findings suggest that it is not necessarily the case and that PARP activation may precede and contribute to free radical and oxidant-induced injury. This study evaluated the effect of PARP inhibition on oxidative-nitrosative stress in diabetic peripheral nerve, vasa nervorum, aorta, and high glucose-exposed human Schwann cells. In vivo experiments were performed in control rats and streptozocin (STZ)-induced diabetic rats treated with and without the PARP inhibitor 3-aminobenzamide (ABA) (30 mg . kg(-1) . day(-1) i.p. for 2 weeks after 2 weeks of untreated diabetes). Human Schwann cells (HSC) (passages 7-10; ScienCell Research Labs) were cultured in 5.5 or 30 mmol/l glucose with and without 5 mmol/l ABA. Diabetes-induced increase in peripheral nerve nitrotyrosine immunoreactivity, epineurial vessel superoxide and nitrotyrosine immunoreactivities, and aortic superoxide production was reduced by ABA. PARP-1 (Western blot analysis) was abundantly expressed in HSC, and its expression was not affected by high glucose or ABA treatment. High-glucose-induced superoxide production and overexpression of nitrosylated and poly(ADP-ribosyl)ated protein, chemically reduced amino acid-(4)-hydroxynonenal adducts, and inducible nitric oxide synthase were decreased by ABA. We concluded that PARP activation contributes to superoxide anion radical and peroxynitrite formation in peripheral nerve, vasa nervorum, and aorta of STZ-induced diabetic rats and high- glucose-exposed HSC. The relations between oxidative-nitrosative stress and PARP activation in diabetes are bi- rather than unidirectional, and PARP activation cannot only result from but also lead to free radical and oxidant generation.
聚（ADP - 核糖）聚合酶（PARP）激活是糖尿病并发症发病机制中的一个重要因素，被认为是氧化 - 亚硝化应激的下游效应器。然而，最近的一些研究结果表明情况并非一定如此，PARP激活可能先于自由基和氧化剂诱导的损伤并促成这种损伤。本研究评估了PARP抑制对糖尿病周围神经、神经滋养血管、主动脉以及高糖处理的人雪旺细胞中氧化 - 亚硝化应激的影响。体内实验在对照大鼠和链脲佐菌素（STZ）诱导的糖尿病大鼠中进行，糖尿病大鼠在未经治疗2周后，分别给予和不给予PARP抑制剂3 - 氨基苯甲酰胺（ABA）（30 mg·kg⁻¹·天⁻¹，腹腔注射，持续2周）。人雪旺细胞（HSC）（第7 - 10代；ScienCell Research Labs）在5.5或30 mmol/L葡萄糖中培养，分别添加和不添加5 mmol/L ABA。ABA可降低糖尿病诱导的周围神经硝基酪氨酸免疫反应性、神经外膜血管超氧化物和硝基酪氨酸免疫反应性以及主动脉超氧化物生成。PARP - 1（蛋白质印迹分析）在HSC中大量表达，其表达不受高糖或ABA处理的影响。ABA可降低高糖诱导的超氧化物生成、亚硝基化和聚（ADP - 核糖基）化蛋白的过表达、化学还原氨基酸 - （4） - 羟基壬烯醛加合物以及诱导型一氧化氮合酶。我们得出结论，PARP激活促成了STZ诱导的糖尿病大鼠周围神经、神经滋养血管和主动脉以及高糖处理的HSC中超氧阴离子自由基和过氧亚硝酸盐的形成。糖尿病中氧化 - 亚硝化应激与PARP激活之间的关系是双向而非单向的，PARP激活不仅可由自由基和氧化剂生成导致，还可引发自由基和氧化剂生成。
