Diabetic endothelial dysfunction:: the role of poly(ADP-ribose) polymerase activation
Diabetic endothelial dysfunction:: the role of poly(ADP-ribose) polymerase activation
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DOI：
10.1038/83241
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发表时间：
2001-01-01
期刊：
影响因子：
82.9
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Soriano, FG;Virág, L;Szabó, C
糖尿病患者经常患有视网膜病、肾病、神经病和加速动脉粥样硬化。内皮功能的丧失先于这些血管改变。在此，我们报道聚（ADP-核糖）聚合酶（PARP）的激活是糖尿病内皮功能障碍发病机制的重要因素。用链脲佐菌素破坏小鼠的胰岛细胞会引起高血糖、血管内氧化剂产生、DNA链断裂、PARP激活和内皮依赖性血管舒张的选择性丧失。尽管严重高血糖持续存在，但在胰岛破坏后开始使用新型强效 PARP 抑制剂进行治疗，仍维持了正常的血管反应性。在高葡萄糖中培养的内皮细胞会产生活性氮和氧，从而导致单链 DNA 断裂、PARP 激活以及相关的代谢和功能损伤。在 PARP 缺陷细胞中，基础和高葡萄糖诱导的核因子 kappaB 激活受到抑制。我们的结果表明 PARP 可能是治疗糖尿病内皮功能障碍的新药物靶点。
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.