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ROLE OF S100A8 AND S100A9 ALARMINS IN COXSACKIEVIRUS B3-INDUCED MYOCARDITIS
1398 JACC April 5, 2016 Volume 67, Issue 13
Heart Failure and Cardiomyopathies ROLE OF S100A8 AND S100A9 ALARMINS IN COXSACKIEVIRUS B3-INDUCED MYOCARDITIS Poster Contributions Poster Area, South Hall A1 Saturday, April 02, 2016, 3:45 p.m.-4:30 p.m. Session Title: Heart Failure and Cardiomyopathies: Basic Abstract Category: 25. Heart Failure and Cardiomyopathies: Basic Presentation Number: 1138-092 Authors: Carsten Tschoepe, Irene Müller, Thomas Vogl, Burkert Pieske, Sophie Van Linthout, Charité, Berlin, Germany, Berlin
Background: The alarmins S100A8 and S100A9, which preferentially form the S100A8/S100A9 heterodimer, are danger-associated molecular pattern molecules and have been shown to be of importance in several cardiovascular disorders. Their role in myocarditis has not been explored yet. The aim of the present study was to investigate the role of S100A8/S100A9 in patients with Coxsackievirus B3 (CVB3)-induced myocarditis and in an experimental CVB3-induced myocarditis mouse model.
Methods: S100A8 and S100A9 mRNA expression was analyzed in endomyocardial biopsies of CVB3+ patients, who eliminated the virus over time. S100A9 knock down (-/-) and wild-type (wt) C57BL/6 mice were i.p. infected with 5 x 10e5 plaque forming units of CVB3 (Nancy strain). A subgroup of S100A9-/- CVB3 mice was additionally i.p. injected with S100A8 every 2 days. Seven days after infection, mice were hemodynamically characterized and left ventricles (LV) were isolated for molecular biology.
Results: S100A8 and S100A9 mRNA expression in endomyocardial biopsies dropped over time in CVB3+ patients who spontaneously healed. Moreover, LV S100A8 and S100A9 mRNA expression was 13.4-fold and 12.1-fold increased in CVB3-infected versus control mice (p<0.05), respectively. S100A9-/- CVB3 mice exhibited an improved LV function compared to CVB3 wt mice. In addition, S100A9-/- CVB3 mice displayed a 1.2-fold (p<0.05) lower CVB3 copy number versus their wt CVB3 littermates. I.p. application of S100A8 in S100A9-/CVB3 mice induced the CVB3 copy number by 3.8-fold (p<0.05) versus S100A9-/- CVB3 mice. In HL-1 cardiomyocytes, S100A8 and S100A9 supplementation led to a 1.8-fold and 1.7-fold (p<0.05) increase in CVB3 copy number, respectively, and a 1.3-fold and 1.1-fold (p<0.05) higher caspase 3/7 activity, respectively. Supplementation of S100A8, S100A9 or S100A8/A9 to CVB3-infected cardiac fibroblasts induced CVB3 mRNA expression by 1.2-fold (p<0.05) each. In addition, S100A8 and S100A9 enhanced alpha-SMA mRNA expression by 1.3-fold each (p<0.05) in CVB3-infected cardiac fibroblasts. Conclusions: This study provides first evidence that the alarmins S100A8 and S100A9 are involved in CVB3-induced myocarditis.
Heart Failure and Cardiomyopathies ROLE OF S100A8 AND S100A9 ALARMINS IN COXSACKIEVIRUS B3-INDUCED MYOCARDITIS Poster Contributions Poster Area, South Hall A1 Saturday, April 02, 2016, 3:45 p.m.-4:30 p.m. Session Title: Heart Failure and Cardiomyopathies: Basic Abstract Category: 25. Heart Failure and Cardiomyopathies: Basic Presentation Number: 1138-092 Authors: Carsten Tschoepe, Irene Müller, Thomas Vogl, Burkert Pieske, Sophie Van Linthout, Charité, Berlin, Germany, Berlin
Background: The alarmins S100A8 and S100A9, which preferentially form the S100A8/S100A9 heterodimer, are danger-associated molecular pattern molecules and have been shown to be of importance in several cardiovascular disorders. Their role in myocarditis has not been explored yet. The aim of the present study was to investigate the role of S100A8/S100A9 in patients with Coxsackievirus B3 (CVB3)-induced myocarditis and in an experimental CVB3-induced myocarditis mouse model.
Methods: S100A8 and S100A9 mRNA expression was analyzed in endomyocardial biopsies of CVB3+ patients, who eliminated the virus over time. S100A9 knock down (-/-) and wild-type (wt) C57BL/6 mice were i.p. infected with 5 x 10e5 plaque forming units of CVB3 (Nancy strain). A subgroup of S100A9-/- CVB3 mice was additionally i.p. injected with S100A8 every 2 days. Seven days after infection, mice were hemodynamically characterized and left ventricles (LV) were isolated for molecular biology.
Results: S100A8 and S100A9 mRNA expression in endomyocardial biopsies dropped over time in CVB3+ patients who spontaneously healed. Moreover, LV S100A8 and S100A9 mRNA expression was 13.4-fold and 12.1-fold increased in CVB3-infected versus control mice (p<0.05), respectively. S100A9-/- CVB3 mice exhibited an improved LV function compared to CVB3 wt mice. In addition, S100A9-/- CVB3 mice displayed a 1.2-fold (p<0.05) lower CVB3 copy number versus their wt CVB3 littermates. I.p. application of S100A8 in S100A9-/CVB3 mice induced the CVB3 copy number by 3.8-fold (p<0.05) versus S100A9-/- CVB3 mice. In HL-1 cardiomyocytes, S100A8 and S100A9 supplementation led to a 1.8-fold and 1.7-fold (p<0.05) increase in CVB3 copy number, respectively, and a 1.3-fold and 1.1-fold (p<0.05) higher caspase 3/7 activity, respectively. Supplementation of S100A8, S100A9 or S100A8/A9 to CVB3-infected cardiac fibroblasts induced CVB3 mRNA expression by 1.2-fold (p<0.05) each. In addition, S100A8 and S100A9 enhanced alpha-SMA mRNA expression by 1.3-fold each (p<0.05) in CVB3-infected cardiac fibroblasts. Conclusions: This study provides first evidence that the alarmins S100A8 and S100A9 are involved in CVB3-induced myocarditis.