Rapamycin ameliorates experimental autoimmune myocarditis
Rapamycin ameliorates experimental autoimmune myocarditis
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DOI：
10.1536/ihj.46.513
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发表时间：
2005-05-01
影响因子：
1.5
通讯作者：
Izumi, T
中科院分区：
文献类型：
--
作者：
Maeda, K;Shioi, T;Izumi, T
肌球蛋白诱导的大鼠自身免疫性心肌炎是人类扩张型心肌病的一种模型。雷帕霉素是一种有效的免疫抑制剂，可以特异性地灭活哺乳动物的雷帕霉素(MTOR)。为了研究mTOR在自身免疫性心肌炎中的作用，我们用心肌肌球蛋白免疫的大鼠注射了雷帕霉素。肌球蛋白免疫大鼠心脏组织中mTOR靶点p70核糖体S6激酶1(S6K1)的磷酸化水平增加了6.9倍。雷帕霉素(2 mg/kg/d)可完全抑制S6K1和S6的磷酸化。肌球蛋白免疫大鼠心脏组织中IL-1β、干扰素-γ、IL-2或肿瘤坏死因子-αmRNA的含量显著增加，雷帕霉素显著抑制细胞因子基因的表达。雷帕霉素提高了大鼠的存活率，并保护了心功能。肌球蛋白免疫大鼠血浆脑利钠肽水平升高4.7倍，雷帕霉素可抑制血浆脑利钠肽水平升高。肌球蛋白免疫组大鼠心脏重量/胫骨长度比对照组增加1.81+/-0.06倍，雷帕霉素可抑制心脏重量的增加。雷帕霉素可减轻心肌细胞浸润和纤维化程度。肌球蛋白免疫的大鼠非核细胞中磷酸化S6的数量增加，雷帕霉素可显著改善自身免疫性心肌炎大鼠的心肌损伤并保护心功能。
Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian tat-get of rapamycin (mTOR).To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1 beta, interferon-gamma, interleukin-2, Or tumor necrosis factor-alpha mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 +/- 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin Suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating rnononuclear cells in vehicle-treated myosin-immunized rats.Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.