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

TNF-a 对慢性炎症性疾病血管功能障碍发展的独立影响的重要性

• 批准号: 274153991
• 负责人: Dr. Franziska Bollmann
• 金额: --
• 依托单位: Post-Transcriptional Gene Expression Group
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/274153991?language=en
• 关键词: Importance; TNF; independent; effects; development

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.

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%的总人口。该疾病与心血管疾病的死亡率增加相关，心血管疾病是由增强的动脉粥样硬化和血栓形成事件引起的，这些事件不能用年龄、性别、高胆固醇血症或糖尿病等传统风险因素来解释。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风险因素。到目前为止，还不完全清楚RA患者中促炎介质如肿瘤坏死因子-α（TNF-α）的异常表达以何种方式促成这种心血管风险。串联锌指蛋白Tristetraprolin（TTP）是一种RNA结合蛋白，其通过结合富含AU的元件促进靶mRNA（例如TNF-α）的去腺苷酸化和衰变。缺乏TTP的小鼠表现出巨大的慢性炎症，类似于人类RA。此外，这些小鼠发展出血管功能障碍，已知其是血管壁中动脉粥样硬化变化的最早标志物，并且与RA驱动的全身性炎症有关。研究表明，TNF-α独立的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。在这个奖学金，氧化应激的作用，在慢性炎症性疾病的动脉粥样硬化的形成将进行分析。肿瘤坏死因子-一个独立的因素发展的血管功能障碍-开始动脉粥样硬化的第一个症状-将被强调。这些实验将阐明，哪些细胞类型负责慢性炎症小鼠模型中增强的NADPH氧化酶2表达和活性氧形成，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。这些结果将为潜在机制提供新的见解，这可能会改善RA患者的治疗并降低其心血管风险。