LAUSR

AIMS Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumor necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis. METHODS AND RESULTS Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR-/- mice. In contrast, at 20 weeks of WD plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes. CONCLUSIONS Modulation of inflammation by iRhom2 deficiency attenuated diet induced hyperlipidemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet- induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice. TRANSLATIONAL PERSPECTIVE iRhom2 attenuates shedding of TNF-α selectively from immune cells and therefore has emerged as a potential new target for the treatment of inflammatory diseases. In the present study, we identified iRhom2 as a critical link between inflammation, lipid metabolism, and atherogenesis. Selective iRhom2 inhibition represents a potential treatment strategy to modify atherosclerosis, particularly in the presence of enhanced inflammation as observed with diabetes mellitus or rheumatoid arthritis.