铁素-2 抑制了线粒体的活性氧物种生成和亡应激激酶-1 活性,以维持心脏功能
Qunhua Huang1, Huanjiao Jenny Zhou1, Haifeng Zhang1
1From Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, University School of Medicine, New Haven, CT (Q.H., H.J.Z., H.Z., Y.H., F.J.G., W.M.); Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (H.J.Z., W.M.); Gilead Sciences Inc, Foster City, CA (F.H.-K., P.F., L.Y., L.B., G.R.B.); and Department of Surgery, Yale University School of Medicine, New Haven, CT (G.T.).
Circulation
|January 29, 2015
概括
线粒体硫素2 (Trx2) 缺乏症通过增加氧化应激和亡,导致心力衰竭. 抑制亡应激激酶-1 (ASK1) 显示出治疗扩张性心肌病和心力衰竭的前景.
科学领域:
- 心血管生物学 心血管生物学
- 线粒体医学 线粒体医学
- 细胞降氧信号传递 细胞降氧信号传递
背景情况:
- 硫素2 (Trx2) 是一种重要的线粒体蛋白质,调节细胞氧化还原平衡和生存.
- Trx2抑制了线粒体的活性氧物种 (ROS) 和亡的应激激酶-1 (ASK1) 依赖的亡.
- 线粒体Trx2在心力衰竭病原体中的作用以前没有被研究过.
研究的目的:
- 为了研究线粒体Trx2系统在心力衰竭的发病过程中的作用.
- 为了确定抑制ASK1在扩大心肌病的治疗潜力.
主要方法:
- 对人类心脏样本和Trx2淘汰赛小鼠的西斑和组织学分析.
- 评估心脏功能,线粒体完整性,ROS产量和ATP水平.
- 评估ASK1信号传递和心肌细胞亡.
- 在Trx2淘汰赛小鼠和心肌细胞中使用选择性ASK1抑制剂进行治疗.
主要成果:
- 在心脏扩张性心肌病症患者中观察到Trx2表达的减少和ASK1活动的增加.
- 心脏特异性Trx2淘汰赛小鼠发展了自发扩张性心肌病,线粒体功能障碍和过早死亡.
- 在Trx2淘汰赛小鼠中,ASK1抑制改善了心脏功能,减少了氧化应激,亡和纤维化.
- 在Trx2-缺乏心肌细胞中,ASK1抑制降低了亡和线粒体ROS.
结论:
- 线粒体Trx2通过减轻ROS产生和ASK1依赖的亡,对保持心脏功能至关重要.
- 抑制ASK1是扩张性心肌病和心力衰竭的潜在治疗策略.
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