通过ferroptosis介导的线粒体功能障碍引起的Trastuzumab诱导的心肌病变
Ting Ye1, Wei Yang2, Tielei Gao3
1Department of Pathophysiology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, China.
Free radical biology & medicine
|July 1, 2023
概括
特拉斯图祖马布 (TRZ) 通过诱导铁亡,一种涉及铁和脂质代谢的细胞死亡形式,引起心脏损伤. 抑制铁亡可能会保护心脏免受TRZ诱导的心脏毒性.
科学领域:
- 生物化学 生物化学
- 心脏病学 心脏病学
- 在瘤学瘤学.
背景情况:
- 特拉斯图祖马布 (TRZ) 是治疗HER-2-阳性乳腺癌的重要疗法.
- 特拉斯图祖马布诱导的心脏毒性 (TIC) 限制了其临床应用.
- 人们还没有完全理解TIC的分子机制.
研究的目的:
- 为了研究铁化在TIC中的作用.
- 阐明将TRZ与线粒体功能障碍和铁亡联系起来的分子途径.
主要方法:
- 建立了TIC的体内 (小鼠) 和体外 (心肌细胞) 模型.
- 评估心脏功能,使用心声回声和细胞活力测试.
- 分析了涉及铁和线粒体功能的关键蛋白质和代谢物 (GPx4,4-HNE,MDA,VDAC1,mPTP,MMP,ATP,GSH/GSSG,铁).
- 利用铁酶抑制剂 (Fer-1,DFO) 和基因过度表达 (mitoGPx4) 来评估治疗潜力.
主要成果:
- 通过抑制ErbB2/PI3K/AKT/Nrf2通路,TRZ降低了GPx4和增加了脂质过氧化 (4-HNE,MDA).
- 线粒体4-HNE积累导致VDAC1寡合化,mPTP开放,并降低了MMP和ATP水平.
- TRZ破坏了线粒体的氧化还原平衡和铁的平衡.
- 铁灭菌抑制剂和mitoGPx4过度表达改善了TIC和铁灭菌.
结论:
- 铁酶介导的线粒体功能障碍是TIC背后的一个关键机制.
- 向铁亡途径提供了一个有前途的心脏保护策略,防止TRZ治疗.
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