Endothelial dysfunction in atherosclerosis

一氧化氮和过氧亚硝酸盐是反应性的，短暂的物种，是动脉粥样硬化的重要介质。过氧亚硝酸盐介导的血管损伤的下游途径之一与核酶聚（ADP-核糖）合成酶（PARS）的活化有关。基于体外和体内初步数据，申请人提出PARS途径可能在与动脉粥样硬化相关的内皮功能障碍的发病机制中起作用，并提出研究来直接测试该假设。本项目的第一个目的是建立动脉粥样硬化中PARS激活和相关血管功能障碍的时间过程，并将这些改变与血管系统中活性氮物质的形成相关联。将在动脉粥样硬化变化开始后的不同时间点从小鼠获得血管，所述动脉粥样硬化变化由两种不同的实验模型（颈动脉模型和Apo/E模型）诱导。将使用免疫组织化学研究活性氮物质形成和PARS活化，将使用离体血管腔中的等长张力测量研究血管反应性。该项目的第二个目的是对PARS相关内皮功能障碍的作用进行直接研究，因为它与动脉粥样硬化相关的内皮功能障碍的发展有关。我们将使用两种不同类型的PARS抑制剂进行长期口服治疗，然后评估血管反应性的变化和动脉粥样硬化的进展。我们的研究将为动脉粥样硬化相关的内皮功能障碍提供新的机制信息，这些信息将用于未来新型血管保护剂的设计和商业开发。拟议的商业应用：仅在美国，用于治疗动脉粥样硬化的有效药剂的年预期收入就超过500亿美元。

Nitric oxide and peroxynitrite are reactive, short-lived species that are important mediators of atherosclerosis. One of the downstream pathways of peroxynitrite-mediated vascular injury is related to activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Based on vitro and in vivo preliminary data, the applicants propose that the PARS pathway may play a role in the pathogenesis of the endothelial dysfunction associated with atherosclerosis, and propose studies to directly test this hypothesis. The first aim of the current project is to establish time course of PARS activation and associated vascular dysfunction in atherosclerosis, and to correlate these alterations with reactive nitrogen species formation in the vasculature. Blood vessels will be obtained form mice at various time points after initiation of atherosclerotic changes, induced by two distinct experimental models (collar and Apo/E models). Reactive nitrogen species formation and PARS activation will be investigated using immunohistochemistry, vascular reactivity will be investigated using ex vivo using isometric tension measurements in vascular chambers. The second aim of the project is to perform direct studies into the role of PARS-related endothelial dysfunction, as it relates to the atherosclerosis-associated development of endothelial dysfunction. We will utilize chronic oral treatment with PARS inhibitors of two different classes, followed by evaluation of changes in vascular reactivity and the progress of atherosclerosis. Our studies will provide novel mechanistic information on atherosclerosis-related endothelial dysfunction which will be utilized for the future design and commercial development of novel vasculoprotective agents. PROPOSED COMMERCIAL APPLICATIONS: The annual anticipated revenues for an effective agent for the therapy of atherosclerosis is over 50 billion in the US alone.