Impact of iRhom2 on atherosclerosis

• Applicant: Privatdozentin Dr. Antje Ludwig, since 11/2018
• Subject Area: Cardiology, Angiology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279291856

Tumor necrosis factor (TNF)-alpha is a potent inflammatory mediator that plays an important role in the development of atherosclerosis. It is expressed as a precursor transmembrane protein and subsequently converted into its soluble, bioactive form by TNF-alpha converting enzyme (TACE) mediated shedding. Recently discovered inactive rhomboid protein 2 (iRhom2) is essential for maturation of TACE in immune cells. A genetic knock-out or knock-down of iRhom2 results in a loss of TACE activity and, consequently, in markedly reduced shedding of TNF-alpha in cells involved in atherosclerosis, such as macrophages. iRhom2-deficient mice exhibit reduced serum levels of TNF-alpha in response to inflammatory stimuli, survive otherwise lethal doses of LPS and are protected from the development of inflammatory arthritis. These findings strongly suggest that the iRhom2/TACE/TNF-alpha signaling axis may contribute to atherosclerosis. However to date, this hypothesis has not been tested experimentally. Therefore, the proposed project evaluates the impact of iRhom2 on early and advanced atherosclerotic plaque development in an iRhom2-deficient atherosclerosis mouse model. Complementary, phenotypic and functional characterization of iRhom2-deficient macrophages will be performed in vitro. The pathophysiological role of iRhom2 in coronary artery disease (CAD) will be evaluated in patients with stable CAD and in the setting of an acute coronary event. Taken together, the proposed project aims at characterizing the role of iRhom2 in atherosclerosis and thus contributes to better understanding of inflammatory processes in atherosclerosis and the development of novel therapeutic strategies for the treatment of this disease.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Bernd Hewing, until 11/2018