综合应激反应配对线粒体蛋白转化与氧化应激控制
Guangyu Zhang1, Xiaoding Wang1, Chao Li1
1Division of Cardiology (G.Z., X.W., C.L., Q.L., X.L., T.G.G., Z.V.W.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Circulation
|September 29, 2021
概括
综合应激反应 (ISR) 在心肌梗塞后的再注血损伤期间保护心脏. 通过抑制线粒体蛋白质合成和氧化应激,激活ISR可以减少心脏损伤.
科学领域:
- 心脏病学
- 分子生物学
- 细胞应激反应
背景情况:
- 心肌梗塞是全球主要的死亡原因.
- 冠状动脉再注血虽然可以挽救生命,但可能会导致进一步的心脏损伤 (再注血损伤).
- 综合应激反应 (ISR) 是一个响应干扰的细胞机制.
研究的目的:
- 调查ISR在心肌缺血/再输血 (I/R) 损伤中的作用.
- 探索操纵ISR治疗心肌梗塞的治疗潜力.
主要方法:
- 在体内使用心脏特异性功能增加和丧失模型.
- 通过对冠状动脉进行绑定和再注射诱导心肌I/R.
- 使用心声学评估心脏功能,并分析细胞培养和组织中的分子机制.
- 使用质谱测量来识别ISR蛋白标,并测试药理干预措施.
主要成果:
- 在ISR的PERK (PKR类内内基酶) /eIF2α (真核启动因子2的α子单位) 轴上,I/R显著诱导.
- 激活心脏PERK/ eIF2α信号,可以防止再输血损伤.
- PERK针对的是线粒体复合物I的组合因子NDUFAF2 (NADH:ubiquinone oxidoreductase复合组合因子2),抑制其表达.
- 激活ISR减少了线粒体的活性氧物种,改善了心脏细胞的存活率.
结论:
- 它可以增强心脏细胞的存活率,并减轻再输血损伤.
- 通过选择性抑制线粒体蛋白质合成和减少氧化应激来实现这种保护.
- 在治疗心肌梗塞方面,ISR的药理活性具有临床意义.
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