Reactive nitrogen species and cardiovascular aging

这个试点补助金申请提交探索与衰老相关的血管功能的自由基和氧化剂介导的改变的某些方面。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学调节可能为与衰老相关的血管功能障碍的实验治疗提供新的途径。我们已经获得了初步的数据，在培养的内皮细胞，氧化剂在内皮细胞附近进行触发细胞内级联反应，最终由核酶聚（ADP-核糖）合成酶（PARS）。这导致PARS的激活，PARS启动能量消耗循环，导致细胞功能障碍和内皮一氧化氮生成受损。我们的初步数据还表明，药物抑制或基因失活PARS减少氧化剂介导的内皮损伤的发展。 在目前的试点研究项目中，我们冒险进入衰老领域，探索过氧亚硝酸盐/PARS途径在衰老血管中的重要性。我们的工作假设是，在老化的脉管系统中，由于抗氧化能力降低和氧化剂产生增加，发生活性氮物质形成和PARS活化。在本研究的第一个目的中，通过比较成年和老年大鼠血管中活性氮物质的产生、血管反应性和PARS活化，我们将探索上述途径活化的时间过程。在第二个具体目标中，用PARS的药理学抑制剂长期治疗将解决PARS是否有助于与衰老相关的内皮功能丧失的问题。我们的研究将提供1。衰老相关内皮功能障碍的新机制信息和2.为随后的全额拨款申请提供初步数据，以研究血管老化过程中的过氧硝酸盐/PARS途径。

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.