The antioxidant edaravone attenuates ER-stress-mediated cardiac apoptosis and dysfunction in rats with autoimmune myocarditis
The antioxidant edaravone attenuates ER-stress-mediated cardiac apoptosis and dysfunction in rats with autoimmune myocarditis
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DOI：
10.3109/10715762.2010.499904
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发表时间：
2010-09-01
影响因子：
3.3
通讯作者：
Aizawa, Yoshifusa
中科院分区：
文献类型：
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作者：
Shimazaki, Hiroko;Watanabe, Kenichi;Aizawa, Yoshifusa
实验性自身免疫性心肌炎（EAM）是由肌球蛋白特异性T细胞分泌炎性细胞因子浸润心肌介导的。本研究采用注射猪心肌肌球蛋白的方法制备大鼠EAM模型。免疫后1周，依达拉奉以3或10 mg/kg/天的剂量对大鼠进行腹腔内给药，持续2周。通过血流动力学和超声心动图检测心功能，并进行TUNEL检测。通过蛋白质印迹法测定左心室（LV）NADPH氧化酶亚单位（p47（Phox）和p67（Phox））、促炎细胞因子（TNF-α）、内质网（ER）应激信号蛋白（GRP 78、caspase-12和GADD 153）和促分裂原活化蛋白激酶（MAPK）家族蛋白（磷酸化p38 MAPK和磷酸化JNK）的表达。依达拉奉以剂量依赖性方式改善LV功能。与溶剂组相比，依达拉奉组中心静脉压显著降低，左室射血分数和短轴缩短率显著升高。此外，依达拉奉治疗下调了p47（Phox）、TNF-α、GADD 153、磷酸化p38 MAPK和磷酸化JNK的LV表达。此外，与溶剂组相比，依达拉奉处理的EAM大鼠的LV表达p67（Phox）、GRP 78、caspase-12和TUNEL阳性细胞显著降低。这些结果表明，依达拉奉通过抑制氧化和ER应激以及随后的心脏细胞凋亡来改善EAM的进展。
Experimental autoimmune myocarditis (EAM) is mediated by myocardial infiltration by myosin-specific T-cells secreting inflammatory cytokines. In this study, rat models of EAM were prepared by injection with porcine cardiac myosin. One week after immunization, edaravone was administered intraperitoneally at 3 or 10 mg/kg/day to rats for 2 weeks. Cardiac function was measured by haemodynamic and echocardiographic studies and TUNEL assay was performed. Left ventricular (LV) expression of NADPH oxidase sub-units (p47(Phox) and p67(Phox)), pro-inflammatory cytokines (TNF-alpha), endoplasmic reticulum (ER) stress signalling proteins (GRP78, caspase-12 and GADD153) and mitogen-activated protein kinase (MAPK) family proteins (phospho-p38 MAPK and phospho-JNK) were measured by western blotting. Edaravone improved LV function in a dose-dependent manner. Central venous pressure was significantly low and LV ejection fraction and fractional shortening was significantly high in edaravone groups compared with those in the vehicle group. In addition, edaravone treatment down-regulated LV expressions of p47(Phox), TNF-alpha, GADD153, phospho-p38 MAPK and phospho-JNK. Furthermore, the LV expressions of p67(Phox), GRP78, caspase-12 and TUNEL-positive cells of rats with EAM treated with edaravone were significantly low compared with those of the vehicle group. These findings suggest that edaravone ameliorated the progression of EAM by inhibiting oxidative and ER stress and, subsequently, cardiac apoptosis.