TXNIP/Redd1 signalling and excessive autophagy: a novel mechanism of myocardial ischaemia/reperfusion injury in mice
TXNIP/Redd1 signalling and excessive autophagy: a novel mechanism of myocardial ischaemia/reperfusion injury in mice
复制标题
TXNIP/Redd1信号传导和过度自噬：小鼠心肌缺血/再灌注损伤的新机制
DOI：
10.1093/cvr/cvz152
复制
发表时间：
2020-03-01
影响因子：
10.8
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Gao, Chao;Wang, Rutao;Tao, Ling
自噬不足或过度均可导致细胞死亡，并导致心肌缺血/再灌注（I/R）损伤。然而，控制心脏中自噬的“正确水平”的机制仍然没有确定。硫氧还蛋白相互作用蛋白（TXNIP）是一种促氧化分子，已知有助于I/R损伤。然而，是否以及如何TXNIP可能进一步抑制抑制自噬或促进过度的心脏自噬在I/R heart.Methods和结果野生型或基因操作的成年雄性小鼠进行心肌I/R。I/R时心肌TXNIP升高。心脏特异性TXNIP过表达增加心肌细胞凋亡和心功能不全，而心脏特异性TXNIP敲除显著减轻I/R诱导的细胞凋亡和改善心功能。重要的是，TXNIP过表达显著促进心脏自噬，而TXNIP敲除显著抑制心脏自噬。体外研究表明，在心肌再灌注过程中，TXNIP增加自噬体的形成，但抑制自噬体的清除。Atg 5 siRNA显著降低缺氧/复氧诱导的TXNIP过表达的心肌细胞凋亡。机制上，TXNIP通过增加活性氧（ROS）水平抑制自噬体清除。然而，TXNIP增加的自噬体形成不是由ROS介导的，因为ROS清除剂未能阻断TXNIP过表达心脏中增加的自噬体形成。最后，TXNIP直接相互作用并稳定Redd 1（一种自噬调节剂），导致mTOR抑制和自噬激活。Redd 1敲低显着减少自噬形成和改善I/R损伤在TXNIP过表达hearts.Conclusions我们的研究结果表明，增加TXNIP-Redd 1的表达是一种新的信号通路，有助于I/R损伤夸大过度自噬在再灌注过程中。这些观察促进了我们对心肌I/R损伤机制的理解。
Aims Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the 'right-level' of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated.Methods and results Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts.Conclusions Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.