Irene Müller1, Thomas Vogl1, Kathleen Pappritz1, Kapka Miteva1, Konstantinos Savvatis1, David Rohde1, Patrick Most1, Dirk Lassner1, Burkert Pieske1, Uwe Kühl1, Sophie Van Linthout1, Carsten Tschöpe2. 1. From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.). 2. From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.). carsten.tschoepe@charite.de.
Abstract
BACKGROUND: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
BACKGROUND: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS:S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3mice. Exogenous application of S100A8 to S100A9 knockout CVB3mice induced a severe myocarditis similar to wild-type CVB3mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS:S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
Authors: Carsten Tschöpe; Sophie Van Linthout; Sebastian Jäger; Robert Arndt; Tobias Trippel; Irene Müller; Ahmed Elsanhoury; Susanne Rutschow; Stefan D Anker; Heinz-Peter Schultheiss; Matthias Pauschinger; Frank Spillmann; Kathleen Pappritz Journal: ESC Heart Fail Date: 2020-07-14
Authors: Frank Spillmann; Sophie Van Linthout; Gunther Schmidt; Oliver Klein; Nazha Hamdani; Thomas Mairinger; Florian Krackhardt; Bastian Maroski; Thomas Schlabs; Sajjad Soltani; Stefan Anker; Evgenij V Potapov; Daniel Burkhoff; Burkert Pieske; Carsten Tschöpe Journal: Eur Heart J Date: 2019-07-01 Impact factor: 29.983
Authors: Irene Müller; Lisa Janson; Martina Sauter; Kathleen Pappritz; Sophie Van Linthout; Carsten Tschöpe; Karin Klingel Journal: Viruses Date: 2021-05-12 Impact factor: 5.048
Authors: Irene Müller; Thomas Vogl; Uwe Kühl; Alexander Krannich; Aron Banks; Tobias Trippel; Michel Noutsias; Alan S Maisel; Sophie van Linthout; Carsten Tschöpe Journal: ESC Heart Fail Date: 2020-05-28