The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, 250012, China.
Cardiovasc Drugs Ther. 2012 Apr;26(2):121-30. doi: 10.1007/s10557-012-6372-6.
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.
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.
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.
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.
心肌炎是一种心脏的急性炎症性疾病，常为扩张型心肌病的前身。实验性自身免疫性心肌炎（EAM）已被用作人类心肌炎的模型。本研究旨在探讨 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶抑制剂，瑞舒伐他汀，对 EAM 发展的治疗作用。
通过用鼠心肌α-肌球蛋白重链（MyHc-α（614-629）[Ac-SLKLMATLFSTYASAD-OH]）免疫 BALB/c 小鼠诱导实验性自身免疫性心肌炎。从免疫后第 0 天到第 21 天，高剂量（10mg/kg/天）或低剂量（1mg/kg/天）瑞舒伐他汀或载体通过胃管口服给予 EAM 小鼠。在免疫后第 21 天，进行超声心动图检查，并通过组织病理学评估检测心肌炎的严重程度。通过 ELISA 测量血清肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6 水平。使用苏木精和伊红进行组织病理学检查。通过 Tunel 检查凋亡，用免疫组化法检测心肌中活性半胱天冬酶-3 的表达。
瑞舒伐他汀减轻了心肌炎的组织病理学严重程度。与未经治疗的 EAM 组相比，两种瑞舒伐他汀治疗组的心脏功能均得到改善（LVFS：高剂量瑞舒伐他汀组[组 H]，0.38±0.10%；低剂量瑞舒伐他汀组[组 L]，0.34±0.06%；未经治疗的 EAM 组[组 N]，0.29±0.07%。LVEF：组 H，0.80±0.09%；组 L，0.71±0.07%；组 N，0.68±0.07%）。此外，瑞舒伐他汀治疗降低了 TNF-α（组 H，65.19±7.06pg/ml；组 L，108.20±5.28pg/ml；组 N，239.34±11.65pg/ml）和 IL-6（组 H，14.33±2.15pg/ml；组 L，19.67±3.04pg/ml；组 N，40.39±7.17pg/ml）的表达水平。活性 Caspase-3 的表达率和心肌凋亡与心肌病理学评分呈正相关。
这些结果表明，瑞舒伐他汀的给药可以改善 EAM 进展，抑制心肌细胞凋亡，并保持心输出量，这表明瑞舒伐他汀可能是心肌炎临床治疗的一种有前途的新治疗策略。
