The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes
The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes
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DOI：
10.2337/diabetes.51.2.514
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发表时间：
2002-02-01
期刊：
影响因子：
7.7
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Pacher, P;Liaudet, L;Szabó, C
糖尿病患者表现出糖尿病心肌病和血管并发症的高发病率，这是视网膜病变、肾病和神经病变发展的基础，并增加了高血压、中风和心肌梗死的风险。有新的证据表明，在链脲佐菌素诱导的糖尿病模型中，核酶聚（ADP-，核糖）聚合酶（PARP）的激活对内皮功能障碍的发展有重要作用。我们研究了PARP激活在链脲佐菌素诱导和遗传（非肥胖糖尿病）糖尿病大鼠和小鼠模型心功能不全发病机制中的作用。糖尿病的发展伴随着高血糖症、心脏PARP激活、胸主动脉内皮依赖性血管舒张的选择性丧失和心脏早期舒张功能障碍。在糖尿病发作后1周开始使用新型强效菲啶酮PARP抑制剂PJ 34治疗，恢复了正常的血管反应性并显著改善了心功能障碍，尽管严重高血糖持续存在。PARP抑制的有益作用甚至在停止治疗数周后仍持续存在。因此，PARP激活在糖尿病心血管（心脏和内皮）功能障碍的发病机制中起着重要作用。PARP抑制剂可能对糖尿病心血管并发症的发展发挥有益作用。
Patients with diabetes exhibit a high incidence of diabetic cardiomyopathy and vascular complications, which underlie the development of retinopathy, nephropathy, and neuxopathy and increase the risk of hypertension, stroke, and myocardial infarction. There is emerging evidence that the activation of the nuclear enzyme poly(ADP-,ribose) polymerase (PARP) importantly contributes to the development of endothelial dysfunction in a streptozotocin-induced model of diabetes. We investigated the role of PARP activation in the pathogenesis of cardiac dysfunction in streptozotocin-induced and genetic (nonobese diabetic) models of diabetes in rats and mice. Development of diabetes was accompanied by hyperglycemia, cardiac PARP activation, a selective loss of endothelium-dependent vasodilation in the thoracic aorta, and an early diastolic dysfunction of the heart. Treatment with a novel potent phenanthridinone-based PARP inhibitor, PJ34, starting I week after the onset of diabetes, restored normal vascular responsiveness and significantly improved cardiac dysfunction, despite the persistence of severe hyperglycemia. The beneficial effect of PARP inhibition persisted even after several weeks of discontinuation of the treatment. Thus, PARP activation plays a central role in the pathogenesis of diabetic cardiovascular (cardiac as well as endothelial) dysfunction. PARP inhibitors may exert beneficial effects against the development of cardiovascular complications in diabetes.