Reactive nitrogen species and cardiovascular aging

活性氮与心血管衰老

• 批准号: 6544963
• 负责人: ANITA MARTON
• 金额: $ 7.95万
• 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: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544963
• 关键词: aging; animal old age; atherosclerosis; blood vessels; cardiovascular function; cardiovascular pharmacology; cell death; enzyme activity; enzyme inhibitors; immunocytochemistry; laboratory rat; male; mature animal; pentosyltransferase; peroxynitrites; vascular endothelium; vascular resistance

This pilot grant application is submitted to explore certain aspects of free radical and oxidant mediated alterations of vascular function associated with aging. Endothelial injury and vascular dysfunction associated with aging is related to local, free radical-related processes, and plays a role in the pathogenesis of various vascular complications associated with aging (including atherosclerosis). Pharmacological modulation of this endothelial cell death and injury may provide novel avenues for the experimental therapy for the vascular dysfunction associated with aging. We have obtained preliminary data in cultered endothelial cells that oxidants proceeded in the vicinity of endothelial cells trigger an intracellular cascade culminating governed by the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in activation of PARS which initiates an energy consuming cycle, with resultant cell dysfunction and impaired endothelial nitric oxide generation. Our preliminary data also demonstrated that pharmacological inhibition or genetic inactivation of PARS reduces the development of oxidant- mediated endothelial injury. In the current pilot research project we venture into the area of aging to explore the importance of the peroxynitrite/PARS pathway in aging blood vessels. Our working hypothesis is that in the aging vasculature, due to the reduced anti- oxidant capacity, and the increased oxidant generation, reactive nitrogen species formation and PARS activation occurs. In the first aim of the study, by comparing reactive nitrogen species generation, vascular reactivity and PARS activation in the blood vessels from adult and aged rats, we will explore the time course of the activation of the above described pathway. In the second specific aim, chronic treatment with pharmacological inhibitors of PARS will address the question whether PARS contributes to the loss of endothelial function associated with aging. Our studies will provide 1. novel mechanistic information on aging-related endothelial dysfunction and 2. preliminary data for a subsequent full grant application to study the peroxynitrate/PARS pathway in the process of vascular aging.

这项试点拨款申请是为了探索与衰老相关的自由基和氧化剂介导的血管功能变化的某些方面。与衰老相关的内皮损伤和血管功能障碍与局部的自由基相关过程有关，并在与衰老相关的各种血管并发症(包括动脉粥样硬化)的发病机制中发挥作用。这种内皮细胞死亡和损伤的药理调节可能为实验治疗与衰老相关的血管功能障碍提供新的途径。我们已经在培养的内皮细胞中获得了初步的数据，氧化剂在内皮细胞附近进行的氧化剂触发了由核酶多(ADP-核糖)合成酶(PARS)控制的细胞内级联反应。这会导致PARs的激活，从而启动能量消耗循环，从而导致细胞功能障碍和内皮一氧化氮的生成受损。我们的初步数据还表明，PARs的药理抑制或遗传失活可以减少氧化剂介导的内皮损伤的发展。在目前的先导性研究项目中，我们冒险进入衰老领域，以探索过氧亚硝酸盐/PARS途径在血管老化中的重要性。我们的工作假设是，在衰老的血管系统中，由于抗氧化能力降低，氧化剂生成增加，活性氮物种的形成和PARS的激活发生。本研究的第一个目的是通过比较成年大鼠和老年大鼠血管中活性氮物种的生成、血管反应性和PARS的激活，来探索上述途径激活的时间进程。在第二个具体目标中，使用PARS的药物抑制剂进行慢性治疗将解决PARS是否导致与衰老相关的内皮功能丧失的问题。我们的研究将提供1.与衰老相关的内皮功能障碍的新的机制信息，2.为随后的全额拨款申请提供初步数据，以研究血管衰老过程中的过氧硝酸盐/PARS途径。