PURPOSE: Myocarditis is an acute inflammatory disease of the heart and is often a precursor of dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis. The purpose of this study was to investigate the therapeutic role of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on the development of EAM. METHODS: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with murine cardiac α-myosin heavy chain (MyHc-α(614-629) [Ac-SLKLMATLFSTYASAD-OH]). High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) rosuvastatin or vehicle was administered orally by gastric gavage to mice with EAM from day 0 to day 21 after immunization. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was detected by histopathological evaluation. Levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by ELISA. Histopathology was performed using haematoxylin and eosin. With apoptosis examined by Tunel, the expression of active caspase-3 in myocardium was investigated by immunohistochemistry. RESULTS: Rosuvastatin attenuated the histopathological severity of myocarditis. Cardiac function was improved in the two rosuvastatin-treated groups compared to the non-treated EAM group (LVFS: high-dose rosuvastatin group [group H], 0.38 ± 0.10%; low-dose rosuvastatin group [group L], 0.34 ± 0.06%; non-treated EAM group [group N], 0.29 ± 0.07%. LVEF: group H, 0.80 ± 0.09%; group L, 0.71 ± 0.07%; group N, 0.68 ± 0.07%). Furthermore, treatment with rosuvastatin decreased the expression levels of TNF-α (group H, 65.19 ± 7.06 pg/ml; group L, 108.20 ± 5.28 pg/ml; group N, 239.34 ± 11.65 pg/ml) and IL-6 (group H, 14.33 ± 2.15 pg/ml; group L, 19.67 ± 3.04 pg/ml; group N, 40.39 ± 7.17 pg/ml). The rates of expression of active Caspase-3 and myocardial apoptosis were positively correlated with the scores for myocardial pathology. CONCLUSIONS: These results demonstrate that administration of rosuvastatin can ameliorate EAM progression, inhibit apoptosis of cardiomyocytes, and preserve cardiac output, and they also suggest rosuvastatin may be a promising novel therapeutic strategy for the clinical treatment of myocarditis.
PURPOSE:Myocarditis is an acute inflammatory disease of the heart and is often a precursor of dilated cardiomyopathy. Experimental autoimmune myocarditis (EAM) has been used as a model for humanmyocarditis. The purpose of this study was to investigate the therapeutic role of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, rosuvastatin, on the development of EAM. METHODS: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with murine cardiac α-myosin heavy chain (MyHc-α(614-629) [Ac-SLKLMATLFSTYASAD-OH]). High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) rosuvastatin or vehicle was administered orally by gastric gavage to mice with EAM from day 0 to day 21 after immunization. On day 21 after immunization, echocardiography was carried out and the severity of myocarditis was detected by histopathological evaluation. Levels of serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by ELISA. Histopathology was performed using haematoxylin and eosin. With apoptosis examined by Tunel, the expression of active caspase-3 in myocardium was investigated by immunohistochemistry. RESULTS:Rosuvastatin attenuated the histopathological severity of myocarditis. Cardiac function was improved in the two rosuvastatin-treated groups compared to the non-treated EAM group (LVFS: high-dose rosuvastatin group [group H], 0.38 ± 0.10%; low-dose rosuvastatin group [group L], 0.34 ± 0.06%; non-treated EAM group [group N], 0.29 ± 0.07%. LVEF: group H, 0.80 ± 0.09%; group L, 0.71 ± 0.07%; group N, 0.68 ± 0.07%). Furthermore, treatment with rosuvastatin decreased the expression levels of TNF-α (group H, 65.19 ± 7.06 pg/ml; group L, 108.20 ± 5.28 pg/ml; group N, 239.34 ± 11.65 pg/ml) and IL-6 (group H, 14.33 ± 2.15 pg/ml; group L, 19.67 ± 3.04 pg/ml; group N, 40.39 ± 7.17 pg/ml). The rates of expression of active Caspase-3 and myocardial apoptosis were positively correlated with the scores for myocardial pathology. CONCLUSIONS: These results demonstrate that administration of rosuvastatin can ameliorate EAM progression, inhibit apoptosis of cardiomyocytes, and preserve cardiac output, and they also suggest rosuvastatin may be a promising novel therapeutic strategy for the clinical treatment of myocarditis.
Authors: Joshua A Walker; Graham A Beck; Jennifer H Campbell; Andrew D Miller; Tricia H Burdo; Kenneth C Williams Journal: J Am Heart Assoc Date: 2015-07-16 Impact factor: 5.501