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

• Applicant: Dr. Franziska Bollmann
• Subject Area: Pharmacology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274153991

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Perry J. Blackshear