摘要
目的探讨阿托伐他汀对病毒性心肌炎的心肌保护作用及机制。
方法以柯萨奇病毒B3m(CVB3m)诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。143只小鼠随机分为正常组(n=18),病毒组(n=60),阿托伐他汀对照组(n=15),阿托伐他汀治疗组(n=50)。正常组组和阿托伐他汀对照组腹腔无菌注射不含病毒的Eagel's培养液0.3ml。病毒组与阿托伐他汀治疗组腹腔单次接种0.3ml X 3×103 PFU/mL CVB3m。阿托伐他汀治疗组给予阿托伐他汀每天10mg/kg/d,病毒组给予等体积饮用水,分别以灌胃器给药,连续用药2周。用药后3、7、10、14、21、30天,检测超声心动图、苏木素-伊红染色(H&E, hematoxylin-eosine)观察心肌组织炎症浸润程度,电镜观察心肌心肌细胞及各种细胞器的变化。western blot及逆转录酶PCR (reverse transcriptase-Polymerase Chain Reaction, RT-PCR)方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法(terminal-deoxynucleotidyl transferase mediated dUTP nick end labeling,脱氧核苷酸末端转移酶介导的dUTP末端缺口标记法)检测心肌细胞凋亡情况,酶联免疫吸附测定(ELISA, enzyme linked immunosorbent assay)方法检测血清心肌肌钙蛋白I (cardiac troponinl,cTnI)水平。
结果发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡;7-14天为死亡高峰。病毒组小鼠心脏超声提示射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。阿托伐他汀干预后显著提高病毒性心肌炎小鼠生存率(病毒组:治疗组为59.2%:87%,P=0.008)。阿托伐他汀治疗组可以改善小鼠心脏射血分数(病毒组比治疗组:第7天:69.82%:78.99%P<0.01;第14天:74.85%:83.50%P<0.01;第21天:70.78%:82.32%P<0.01;第30天:76.47%:82.69% P<0.01)。阿托伐他汀治疗组较病毒组可以明显减轻心肌组织炎症浸润,心肌病理组织学积分在第10,14,21,30天阿托伐他汀治疗组较病毒组减少。阿托伐他汀治疗组较病毒组显著降低各个时间点血清cTnI水平(病毒组:阿托伐他汀治疗组第7天:3.62:1.65 P=0.042;第10天7.03:2.83 P<0.01;第14天6.30:2.20 P=0.034;第21天2.73:0.63P=0.007)。在阿托伐他汀治疗组Fas蛋白及mRNA表达减少,细胞凋亡率也明显减少(病毒组:阿托伐他汀治疗组第14天12.36:4.82 P=0.006;第21天4.33:1.37P=0.019)。
结论:阿托伐他汀能明显降低病毒性心肌炎的死亡率。减少病毒性心肌炎中心肌细胞的损害,减轻组织的病理改变,提高心脏射血功能,促进病情缓解。其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。因此,阿托伐他汀对病毒性心肌炎小鼠有明显的心肌保护作用。病毒性心肌炎小鼠可以从阿托伐他汀的治疗中获益。
目的:强的松是广泛用于临床的一种糖皮质激素药物。本研究拟探讨强的松对Balb/c小鼠病毒性心肌炎的保护作用和机制,以及不同用药时间之间的差别。
方法:以柯萨奇病毒B3诱导的病毒性心肌炎Balb/c小鼠模型为研究对象。303只小鼠随机分为正常组(n=18),强的松对照组(n=15),病毒组(n=60),强的松早期治疗组(n=50),强的松晚期治疗组(n=30),维生素C治疗组(n=50),强的松早期+维生素C治疗组(n=50),强的松晚期+维生素C治疗组(n=30)。强的松治疗组给予强的松每天lmg/kg,早期治疗组为攻毒后第三天用药,晚期治疗组为攻毒后第10天给药;未治疗组给予等体积饮用水,分别以灌胃器给药,连续用药2周。未攻毒同周龄Balb/c小鼠为正常对照组,未攻毒给予强的松每天1mg/kg为强的松药物对照组。用药后3、7、10、14、21、30天,检测超声心动图、HE染色观察心肌组织炎症浸润程度,电镜观察心肌胶原纤维、心肌细胞及各种细胞器的变化。western blot及RT-PCR方法检测心肌Fas蛋白及mRNA表达水平,TUNEL法检测心肌细胞凋亡情况,ELISA方法检测血清cTnI水平。
结果:发现病毒性心肌炎小鼠攻毒后第3天开始出现症状,饮水进食减少,体重减轻。随后症状逐渐加重,第4天出现死亡;7-14天为死亡高峰。病毒组小鼠心脏超声提示心脏射血分数在第7天开始出现异常下降,光镜与电镜可以观察到明显的病理改变。TUNEL法检测发现凋亡细胞增多,心肌炎小鼠血清cTnI增高。强的松干预后显著提高病毒性心肌炎小鼠生存率(病毒组59.2%;强的松早期+维生素C治疗组81.8% P=0.028),维生素C治疗组生存率为71.9%,未见显著性差异。病毒组小鼠心脏射血分数第7天时早期强的松+维生素C组EF显著升高(P=0.038),第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组心脏射血分数显著升高(P=0.005;0.008),第30天时与病毒组比较,早期强的松治疗组射血分数显著升高(P=0.048)。收缩末期直径及容积第21天时与病毒组比较,早期强的松治疗组,早期强的松+维生素C组,晚期强的松+维生素C组的收缩末期直径明显减少(P=0.036;0.003;0.029)。强的松各治疗组较病毒组可以减轻心肌组织炎症浸润。与病毒性组比较,在第10天强的松早期治疗组、维生素治疗组与早期强的松+维生素C组cTnI明显减低(P<0.01;P=0.48;P<0.01),第14天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.015;0.013),第21天时间点上强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.043;0.032)。与维生素C治疗组比较,在第10天强的松早期治疗组与早期强的松+维生素C组cTnI明显减低(P=0.009;0.005)。细胞凋亡率与病毒性组比较在第7天强的松早期治疗组与早期强的松+维生素C组凋亡指数分明显减低(P<0.01;P<0.01),第21天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P=0.029;P=0.022;P<0.01;P<0.01),第30天时间点上强的松早期治疗组与早期强的松+维生素C组,强的松晚期治疗组与晚期强的松+维生素C组的凋亡指数明显减低(P<0.01;0.0111;0.0161;0.0117)。在强的松+维生素C治疗组Fas蛋白及mRNA表达减少。
结论:强的松与维生素C联用可改善病毒性心肌炎小鼠生存率,提高心功能及改善组织病理学表现,其机制可能通过下调Fas转录及分子表达抑制心肌细胞凋亡有关。表明强的松与维生素C联用对病毒性心肌炎小鼠有明显的心肌保护作用。在病毒性心肌炎小鼠可以从强的松的治疗中获益,第三天应用效果较第十天应用效果好。
Objective:The goal of this study was to investigate the therapeutic benefits of atorvastatin on Coxsackie virus B3-induced myocarditis in Balb/c mice.
Method:143 male 4-week-old Balb/c mice were divided into four groups randomly, including nomal control group (mice were administered Eagle's minimal essential medium 18 mice), virus group (virus solution intraperitoneally,3×103 PFU/mL,60 mice), atorvastatin control group (atorvastatin 10mg/kg/day,15 mice) and atorvastatin treatment group (virus plus atorvastatin 10mg/kg/day,50 mice). Atorvastatin was given 3 days after viral challenge and treatment lasted for 14 days in the atorvastatin control group and atorvastatin treatment group. Echocardiograms were examined on days 3,7, 10,14,21, and 30 after virus inoculation (same days for the atorvastatin control group). Blood samples were collected for cardiac troponin I detection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the atorvastatin treatment group. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell apoptosis in the atorvastatin treatment group compared to virus group that did not receive treatment (virus group:atorvastatin treatment group:12.36:4.82 P=0.006 at 14 days; 4.33:1.37 P=0.019 at 21days). The differences in cTnI values between the virus group and atorvastatin treatment group achieve statistical significance, there was decrease in cTnI in the atorvastatin treatment group(virus group:atorvastatin treatment group:3.62:1.65 P=0.042 at 7 days; 7.03:2.83 P<0.01 at 10 days; 6.30:2.20 P=0.034 at 14 days; 2.73:0.63 P=0.007 at 14 days 21 days). RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with atorvastatin.
Conclusion:These results demonstrate that atorvastatin reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of atorvastatin on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
Objective:The goal of this study was to investigate the therapeutic benefits of prednisone on Coxsackie virus B3m-induced myocarditis in Balb/c mice. Discussion the difference between different time of prednisone on viral myocarditis in mice at the medication.
Method:303 male 4-week-old Balb/c mice were divided into eight groups randomly, including nomal control group(Mice were administered Eagle's minimal essential medium, n=18), prednisone group(Mice were administered prednisone(1mg/kg/day) at 3 days, n=15), infected control group(virus solution intraperitoneally,3×103 PFU/mL n=60), group of infected mice with prednisone treatment at early stage(Mice were administered prednisone(1mg/kg/day) at 3 days post-inoculation, n=50), group of infected mice with prednisone treatment at late stage(Mice were administered prednisone(1mg/kg/day) at 10 days post-inoculation, n=30), group of infected mice with prednisone treatment at early stage and Vit C(Mice were administered prednisone at 3 days post-inoculation and Vit C, n=50), group of infected mice with prednisone treatment at late stage and Vit C(Mice were administered prednisone at 10 days post-inoculation and VitC, n=30), group of infected mice with Vit C(Mice were administered VitC n=50). Prednisone was given 3 or 10days after viral challenge and treatment lasted for 14 days. The Echocardiograms were examined on days 3,7,10,14,21, and 30 after virus inoculation. Blood samples were collected for cardiac troponinⅠdetection at the same time. Myocardial inflammation, cell apoptosis and Fas expression were detected by histology and western blot, RT-PCR.
Results:The myocardial histopathological score of mice in each infected group on day 7-10 after infection were significantly higher than that in normal control group, but no significant difference in each infected group. On day 14 after infecteion, the myocardial histopathologic socre of mice with Prednisone treatment at early stage were significantly lower than that in other infected groups, H&E staining and transmission electron microscopy revealed significant improvement of quantitative pathological features in the prednisone treatement at early stage. Immunohistochemical microscopy also showed a marked decrease in the level of cardiac cell Apoptosis in the Prednisone-treated group compared to infected animals that did not receive treatment. The differences in cTnI values between the virus-challenged animals and prednisone -treated virus-challenged mice achieve statistical significance, there was a trend toward a decrease in cTnl in the Prednisone-treated mice.RT-PCR and western blotting revealed that the virus induced marked increases in Fas mRNA and protein expression, which could be prevented by treatment with Prednisone.
Conclusion:Prednisone and vit c therapy at early stage ameliorated the severity of myocardial lesions in viral myocarditis, especially used in early stage of the disease. Prednisone and vit c therapy reduced the inflammatory infiltration in myocardium, inhibited autoimmune response. Prednisone therapy reduced the lever of serum cardiac troponin I in viral myocarditis. These results demonstrate that Prednisone and vit c reduces the histological and functional severity of CVB3m-induced myocarditis, and inhibits apoptosis and Fas expression in the myocardium of CVB3m-infected mice. The therapeutic benefits of prednisone on myocarditis may be explained, at least in part, by inhibition of Fas expression and inhibition of cell apoptosis.
引文
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1. Haas GJ. Etiology, evaluation, and management of acute myocarditis. Cardiology in Review 2001;9(2):88-95.
2. Feldman AM, McNamara D. Myocarditis. The New England Journal of Medicine 2000;343(19):1388-98.
3. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, et al.Sudden unexpected death in persons less than 40 years of age. American Journal of Cardiology 1991;68(13):1388-92.
4. Ellis CR, Di Salvo T. Myocarditis:basic and clinical aspects. Cardiol Rev.2007 Jul-Aug;15(4):170-7.
5. Brunetti L, DeSantis ER. Treatment of viral myocarditis caused by coxsackievirus B. Am J Health Syst Pharm.2008 Jan 15;65(2):132-7.
6. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral myocarditis mimicking acute myocardial infarction. Journal of the American College of Cardiology 1992;20:85-9.
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