Carmen Hannemann1,2,3, Johannes H Schecker1,2, Alica Brettschneider1,2, Jana Grune2,4, Nicole Rösener1, Andrea Weller1, Verena Stangl1,2, Edward A Fisher3, Karl Stangl1,2, Antje Ludwig1,2,5, Bernd Hewing1,2,6,7,8. 1. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. 2. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany. 3. Division of Cardiology, Department of Medicine, New York University School of Medicine, Hannemann435 East 30th St., 10016 New York, NY, USA. 4. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Institute of Physiology, Charitéplatz 1, 10117 Berlin, Germany. 5. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Klinik für Radiologie, Charitéplatz 1, 10117 Berlin, Germany. 6. Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany. 7. Zentrum für Kardiologie, Kardiologische Gemeinschaftspraxis, Loerstr. 19, 48143, Muenster, Germany. 8. Department of Cardiology III-Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany.
Abstract
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 tumour 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. CONCLUSION: Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice. Published on behalf of the European Society of Cardiology. All rights reserved.
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 tumour 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. CONCLUSION: Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice. Published on behalf of the European Society of Cardiology. All rights reserved.
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