GLP-1改善阿霉素诱导心肌损伤的作用及机制研究

以阿霉素诱导心肌损伤为代表的化疗药物心脏毒性作用是影响癌症患者远期生存的主要因素，目前仍缺乏有效治疗手段。近来研究提示胰高血糖素样肽-1（GLP-1）具有心血管保护作用，但其具体机制尚不明确。我们前期研究发现GLP-1可通过胰高血糖素样肽-1受体（GLP-1R）依赖途径改善阿霉素诱导心肌细胞氧化应激，通过GLP-1R非依赖途径改善阿霉素诱导细胞自噬抑制。同时，我们采用芯片技术发现GLP-1改善阿霉素诱导的细胞自噬抑制与AMPKα2密切相关。因此我们推测：GLP-1通过GLP-1R依赖途径改善阿霉素诱导的心肌细胞线粒体损伤，通过GLP-1R非依赖途径激活AMPK信号通路促进损伤线粒体的自噬清除，协同发挥改善阿霉素诱导心肌损伤的作用。本项目将利用AMPKα2及GLP-1R敲除小鼠、原代心肌细胞研究GLP-1改善阿霉素诱导心肌损伤的作用及机制，为阿霉素诱导心肌损伤的防治提供新的思路和靶点。

Doxorubicin-induced cardiotoxicity (DIC) is the most notorious chemotherapy-induced cardiotoxicity that is the leading cause of morbidity and mortality in cancer survivors, and remains no effective intervention. Recently studies indicated that glucagon-like peptide-1 (GLP-1) exhibit cardiovascular benefits through incompletely characterized mechanisms. Our preliminary studies showed that GLP-1 protects cardiomyocytes against doxorubicin-induced oxidative stress through GLP-1 Receptor (GLP-1R)–dependent pathway. GLP-1 eliminates doxorubicin-induced suppressed autophagy through GLP-1R–independent pathway. Additionally, we found that AMPKα2 is closely related to doxorubicin-induced suppressed autophagy by microarray. We therefore hypothesize that GLP-1 protects cardiac mitochondria against doxorubicin-induced damage through GLP-1R–dependent pathway; GLP-1 eliminates doxorubicin-induced suppressed mitophagy via AMPKα2 through GLP-1R–independent pathway. To prove this hypothesis, this study will utilize AMPK and GLP-1R deficiency mice, and primary cardiomyocytes to investigate the protective role and mechanisms of GLP-1 in DIC in both animal and cellular levels, and thus to provide a new target for DIC prevention and treatment.