Mechanisms of cardiovascular dysfunction in diabetes

糖尿病心血管功能障碍的机制

• 批准号: 6654911
• 负责人: CSABA SZABO
• 金额: $ 41.17万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654911
• 关键词: apoptosis; bioenergetics; cardiovascular injury; clinical research; diabetic angiopathy; diabetic cardiomyopathy; enzyme activity; genetically modified animals; histopathology; human tissue; inflammation; laboratory mouse; laboratory rat; oxidative stress; pathologic process; pentosyltransferase; prediabetic state; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): Diabetes-associated endothelial injury and vascular dysfunction is related to local, free radical-related processes. Pharmacological modulation of this endothelial cell death and injury may provide novel avenues for the experimental therapy of the vascular dysfunction in advanced diabetes. In the prior funding period, we obtained data in cultured endothelial cells showing that oxidants produced in the Vicinity of endothelial cells during hyperglycemia trigger an intracellular cascade culminating governed by the nuclear enzyme poly (ADP-ribose) polymerase (PARP). This results in activation of PARP, which initiates an energy consuming metabolic cycle, with resultant cell dysfunction. Our data also show that high glucose activates the PARP pathway in endothelial cells in vitro. Pharmacological inhibition or genetic inactivation of PARP reduces the development of oxidant- or high glucose mediated endothelial injury. Destruction of functional islet cells with streptozotocin in rats induced chronic hyperglycemia, extravascular production of oxidants, activation of PARP in the endothelium, and a loss of endothelial function. PARP inhibition, starting after the time of islet destruction, maintained and restored normal vascular responsiveness, despite the persistence of severe hyperglycemia. Now we propose mechanistic studies and additional, definitive in vivo studies to establish the role of PARP in diabetic vascular failure. We will establish the molecular triggers leading to PARP activation in diabetes. In addition, we will characterize changes in sentinel markers of endothelial injury, and the role of the PARP pathway. The in vivo studies will be complemented by in vitro studies investigating the mode of high glucose induced PARP activation and cell death in macro- and microvascular endothelial cells. A further aim is to perform studies in chronic rat diabetes models to delineate the role of PARP in the development of retinopathy, nephropathy and neuropathy associated with diabetes mellitus. We will also extend the studies from the vascular dysfunction to the myocardial dysfunction (diabetic cardiomyopathy). The final aim of the study is to investigate the activation of PARP in human microvasculature, and to correlate the degree of PARP activation with the degree of endothelial dysfunction in humans.

描述（由申请人提供）：糖尿病相关内皮损伤和血管功能障碍与局部自由基相关过程有关。通过药物调节内皮细胞的死亡和损伤可能为晚期糖尿病血管功能障碍的实验性治疗提供新的途径。在之前的资助期间，我们在培养的内皮细胞中获得的数据显示，在高血糖期间内皮细胞附近产生的氧化剂触发了由核酶聚（ADP-核糖）聚合酶（PARP）控制的细胞内级联反应。这导致PARP的激活，其启动能量消耗代谢循环，导致细胞功能障碍。我们的数据还表明，高葡萄糖激活PARP途径在内皮细胞在体外。PARP的药理学抑制或基因失活可减少氧化剂或高糖介导的内皮损伤的发生。链脲佐菌素对大鼠功能性胰岛细胞的破坏可诱导慢性高血糖、血管外产生氧化剂、内皮中PARP的激活和内皮功能的丧失。尽管持续存在严重的高血糖症，但在胰岛破坏后开始的PARP抑制维持并恢复了正常的血管反应性。现在，我们提出了机制研究和额外的，明确的体内研究，以确定PARP在糖尿病血管衰竭中的作用。我们将建立导致糖尿病PARP激活的分子触发因素。此外，我们将描述内皮损伤的前哨标记物的变化，以及PARP通路的作用。将通过体外研究补充体内研究，研究高葡萄糖诱导的PARP激活模式和大血管和微血管内皮细胞中的细胞死亡。另一个目的是在慢性大鼠糖尿病模型中进行研究，以描述PARP在糖尿病相关视网膜病变、肾病和神经病变发展中的作用。我们也将研究从血管功能障碍扩展到心肌功能障碍（糖尿病心肌病）。本研究的最终目的是研究人微血管系统中PARP的活化，并将PARP活化程度与人内皮功能障碍程度相关联。