Importance of TNF-a independent effects on the development of a vascular dysfunction in chronic inflammatory diseases

类风湿关节炎(RA)是一种慢性炎症性自身免疫性疾病，在工业化国家中约占总人口的0.5-1%。这种疾病与心血管疾病死亡率的增加有关，心血管疾病是由动脉粥样硬化和血栓事件增加引起的，这些事件不能用年龄、性别、高胆固醇血症或糖尿病等传统危险因素来解释。相反，慢性炎症是这些患者出现心血管事件的重要和独立的危险因素。到目前为止，在RA患者中，促炎症介质如肿瘤坏死因子-a(TNF-a)的异常表达是如何导致这种心血管风险的，目前还不完全清楚。串联锌指蛋白Tristetraprolin(TTP)是一种RNA结合蛋白，通过与富含AU的元素结合，促进靶mRNAs的去烯化和衰变，如肿瘤坏死因子-α。缺乏TTP的小鼠表现出大量的慢性炎症，类似于人类类风湿关节炎。此外，这些小鼠出现血管功能障碍，这种功能障碍被认为是血管壁动脉粥样硬化变化的最早标志，并与RA驱动的全身炎症有关。研究表明，肿瘤坏死因子-a是这些小鼠血管功能障碍的触发因素。TTP缺乏导致NADPH氧化酶2表达增加，从而增加了活性氧物种的数量。活性氧和生物活性一氧化氮的反应改变了血管扩张剂和缩血管药的比例，导致血管功能障碍的形成。在此期间，将分析氧化应激在慢性炎症性疾病中动脉粥样硬化形成中的作用。肿瘤坏死因子-α-血管功能障碍发展的独立因素--动脉粥样硬化开始的第一个症状--将被强调。这些实验将阐明，在慢性炎症小鼠模型中，哪些细胞类型对NADPH氧化酶2表达增强和活性氧形成负责，以及使用特定NADPH氧化酶抑制剂的抗氧化治疗是否减少或阻止小鼠模型中血管功能障碍的形成。这一结果将为了解其潜在的机制提供新的见解，这可能会改善RA患者的治疗，降低他们的心血管风险。

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects approximately 0.5-1 % of the general population in industrialized countries. The disease is associated with an increased mortality from cardiovascular disorders, resulting from enhanced atherosclerotic and thrombotic events that are not explained by the traditional risk factors of age, gender, hypercholesterolemia, or diabetes. Rather, chronic inflammation is an important and independent risk factor for the appearance of cardiovascular events in these patients. Until now it is not completely understood in which way the abnormal expression of pro-inflammatory mediators as tumor necrosis factor-a (TNF-a) in RA patients contribute to this cardiovascular risk. The tandem zinc finger protein Tristetraprolin (TTP) is a RNA-binding protein promoting the deadenylation and decay of target mRNAs for example of TNF-a via binding to AU-rich elements. Mice deficient in TTP show a massive chronic inflammation, resembling human RA. Furthermore, these mice develop a vascular dysfunction that is known to be the earliest marker of atherosclerotic changes in the vessel wall and has been linked to RA-driven systemic inflammation. Studies revealed TNF-a independent mechanisms being the trigger of a vascular dysfunction in these mice. The TTP deficiency leads to an increased expression of NADPH oxidase 2, thus enhancing amounts of reactive oxygen species. The reaction of reactive oxygen species and bioactive nitric oxide shifts the ratio of vasodilators and -constrictors, leading to the formation of vascular dysfunction. During this fellowship, the role of oxidative stress for the formation of atherosclerosis during chronic inflammatory diseases will be analyzed. TNF-a-independent factors for the development of a vascular dysfunction - the first symptom of a beginning atherosclerosis - will be highlighted. The experiments will clarify, which cell types are responsible for the enhanced NADPH oxidase 2 expression and reactive oxygen formation in a chronic inflammation mouse model, as well as whether an anti-oxidative treatment using a specific NADPH oxidase inhibitor reduces or stops the formation of a vascular dysfunction in mouse models. The results will provide new insights into the underlying mechanisms, which may improve the therapy of RA patients and lower their cardiovascular risk.