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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
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MST1通过SIRT3下调调节来调解多克索鲁比诱导的心肌病
Leonardo Schirone1, Daniele Vecchio1, Valentina Valenti2
1Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Cellular and molecular life sciences : CMLS
|August 11, 2023
概括
doxorubicin (DOX) 化疗可以通过激活MST1通路引起心力衰竭,从而降低保护性SIRT3水平. 抑制MST1可以保护心脏免受DOX损伤,为癌症患者提供潜在的治疗策略.
科学领域:
- 心血管生物学 心血管生物学
- 癌症治疗方法 癌症治疗方法
- 分子医学是分子医学.
背景情况:
- 多克索鲁比 (DOX) 是一种重要的化疗剂,但会引起显著的心脏毒性,导致心力衰竭.
- 驱动DOX诱导心肌病的精确分子机制尚不完全理解.
- 河马通路酶MST1与细胞应激反应有关,但其在DOX心脏毒性中的作用尚不清楚.
研究的目的:
- 调查氨酸/氨酸激酶MST1对多克索鲁比诱导的心肌损伤的贡献.
- 阐明将MST1激活与DOX心脏毒性联系起来的分子途径.
- 评估MST1抑制作为预防DOX诱导心脏损伤的潜在策略.
主要方法:
- 使用了C57BL/6J野生型 (WT) 鼠和心肌细胞特异主导负MST1 (DN-MST1) 转基因鼠.
- 每周注射多克索鲁比 (累计剂量18毫克/公斤),然后进行心声学,组织学和生物化学分析.
- 评估MST1信号传递,线粒体功能,SIRT3水平和心肌细胞损伤在体外和体内,包括使用MST1抑制剂XMU-MP-1和SIRT3抑制的实验.
主要成果:
- 多克索鲁比治疗显著激活了心肌细胞中的MST1信号,无论是体外还是体内.
- 接受DOX的WT小鼠患有心脏功能障碍和线粒体异常,在DN-MST1小鼠和用XMU-MP-1治疗的小鼠中预防了这些异常.
- 在WT小鼠中,DOX诱导了线粒体脱甲基酶SIRT3的下调,这种效果被MST1抑制逆转;药理上抑制SIRT3取消了MST1抑制的保护作用.
- 在接受DOX治疗的癌症患者的人类心肌组织中观察到MST1水平升高和SIRT3水平降低.
结论:
- MST1激活是多克索鲁比诱导心脏毒性的关键调解者.
- 通过对线粒体保护因子SIRT3.3的降低调节,MST1有助于DOX诱导的心肌损伤.
- 抑制MST1信号传递是一种有前途的治疗方法,可以减轻癌症患者的多克索鲁比心脏毒性.
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