线粒体介导小檗碱抗阿霉素心肌毒性的相关机制研究

Protection against the cardiotoxicity of doxorubicin (DOX) remains a major concern. Increasing evidence suggests that mitochondrial damage plays an important role in the DOX-induced cardiotoxicity. Our previous study has showed that berberine (Ber) attenuates myocardial apoptosis after DOX exposure via protecting mitochondria transmembrane potential and maintaining adenosine triphosphate (ATP) levels, but the precise mechanisms for the protection of berberine against DOX-induced cardiotoxicity via improving mitochondrial function is not fully investigated. In this study, we will elucidate the underlying mechanism in vivo and in vitro. Rats with chronic cardiomyopathy induced by DOX will be used for experiments. Firstly, we detect the rat survival, and then choose the optimal dose of Berberine. Furthermore, echocardiography, oxidative damage, cardiomyocyte apoptosis, mitochondrial injury and the expression of heme oxygenase-1 （HO-1） will determined. We also isolate neonatal rat cardiomyocytes to analyze the pathways of HO-1-reactive oxygen species (ROS)-respiration chains complexⅠ,Ⅲ,Ⅴ/ uncoupling proteins (UCP)-ATP and HO-1-nuclear respiratory factor (NRF)-1-mitochondrial biogenesis. Finally, the inhibitor of HO-1 or siRNA against HO-1 will be used to clarify the related mechanism by which mitochondrion is involved in the protection of berberine against Dox-triggered cardiotoxicity. These investigations have a great significance for improving the survival in cancer patients treated with DOX.

防治阿霉素心肌毒性一直是医学面临的重要课题。大量研究表明线粒体损伤是阿霉素心肌毒性的重要环节。我们前期研究发现小檗碱可通过增加线粒体膜电位和ATP含量对抗阿霉素心肌毒性，但其保护线粒体的具体作用环节尚不清楚。因此，本课题将从线粒体入手探究小檗碱抗阿霉素心肌毒性的相关机制。首先利用阿霉素慢性心肌毒性大鼠模型，观察小檗碱能否降低模型大鼠死亡率并选择最佳治疗剂量。检测小檗碱对阿霉素引起的大鼠心功能障碍、心肌氧化损伤、凋亡、线粒体损伤以及血红素氧合酶-1表达的影响。进一步采用原代培养心肌细胞，通过测定血红素氧合酶-1-活性氧-线粒体呼吸链复合物Ⅰ、Ⅲ、Ⅴ/解耦联蛋白-三磷酸腺苷和血红素氧合酶-1-核呼吸因子-线粒体生物合成两条途径，同时使用血红素氧合酶-1抑制剂或小分子干扰RNA予验证，以阐明线粒体介导小檗碱抗阿霉素心肌毒性的分子机制。对有效防治阿霉素心肌毒性、提高化疗患者的生存质量具有重要意义。