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

类风湿性关节炎（RA）是一种慢性炎症性自身免疫性疾病，影响工业化国家约0.5- 1%的普通人群。该疾病与心血管疾病死亡率增加相关，心血管疾病是由动脉粥样硬化和血栓形成事件增加引起的，而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一个重要和独立的危险因素。到目前为止，还没有完全了解RA患者中促炎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。串联锌指蛋白tristetrprolin （TTP）是一种rna结合蛋白，通过与富au元素结合，促进靶mrna（如TNF-a）的死烯化和衰变。缺乏TTP的小鼠表现出大量的慢性炎症，类似于人的类风湿性关节炎。此外，这些小鼠出现血管功能障碍，这是已知的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，TNF-a独立机制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的表达增加，从而增加活性氧的数量。活性氧和生物活性一氧化氮的反应改变了血管舒张剂和收缩剂的比例，导致血管功能障碍的形成。本研究将分析慢性炎症性疾病中氧化应激在动脉粥样硬化形成中的作用。血管功能障碍（动脉粥样硬化初期的第一个症状）的发展与tnf -a无关的因素将被强调。实验将阐明，在慢性炎症小鼠模型中，哪种细胞类型负责增强NADPH氧化酶2的表达和活性氧的形成，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。该结果将为RA患者的潜在机制提供新的见解，可能改善RA患者的治疗并降低其心血管风险。

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.