Txnip C247S mutation protects the heart against acute myocardial infarction.
Txnip C247S mutation protects the heart against acute myocardial infarction.
复制标题
Txnip C247S突变保护心脏免受急性心肌梗死
DOI：
10.1016/j.yjmcc.2021.02.013
复制
发表时间：
2021-06
影响因子：
5
通讯作者：
Yoshioka J
中科院分区：
文献类型：
--
作者：
Nakayama Y;Mukai N;Wang BF;Yang K;Patwari P;Kitsis RN;Yoshioka J
硫氧还蛋白相互作用蛋白(TXNIP)是一个在多种人类疾病中具有翻译潜力的新的分子靶点。TXNIP有几个确定的细胞作用，包括与硫氧还蛋白结合，硫氧还蛋白是活性氧物种(ROS)的清除剂。长期以来，体外证据表明TXNIP通过半胱氨酸247(C247)与还原的硫氧还蛋白形成二硫键，从而抑制硫氧还蛋白的抗氧化特性。然而，TXNIP-硫氧还蛋白相互作用的生理意义在很大程度上仍未在体内确定。TXNIP的单一突变C247S取消了TXNIP与硫氧还蛋白的结合。我们用一个不结合硫氧还蛋白的突变体TXNIP的小鼠模型，采用条件诱导的方法，测试了硫氧还蛋白与TXNIP的相互作用是否是TXNIP在心脏中的促氧化或细胞毒性作用所必需的。由于不能抑制硫氧还蛋白，TXNIP C247S在细胞中的过表达导致ROS减少。与野生型TXNIP表达细胞相比，表达TXNIP C247S的细胞内ROS水平降低，从而降低了低氧(1%O2，24小时)对TXNIP的杀伤作用。然后在动物模型上评估心肌缺血损伤。与对照组相比，心肌细胞特异性TXNIP C247S敲入小鼠的存活率更高，心肌梗死后的梗塞面积更小。不存在TXNIP对硫氧还蛋白的抑制作用可提高心肌细胞线粒体的抗氧化能力，从而保护心脏免受心肌梗死引起的氧化损伤。此外，无偏的RNA测序筛选表明，低氧诱导因子1信号通路参与了TXNIP C247S介导的心肌保护机制。TXNIP是一种含有半胱氨酸的氧化还原蛋白，通过二硫键转换机制在成年心肌细胞中强有力地调节硫氧还蛋白系统。我们的结果提供了直接的体内证据，证明TXNIP对氧化还原状态的调节是缺血应激下心肌动态平衡的重要组成部分。
Thioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo. A single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip’s pro-oxidative or cytotoxic effects in the heart. Overexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 hrs)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following MI compared to control animals. The absence of Txnip’s inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by myocardial infarction. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms. Txnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.
登录
查看更多内容
影响因子：
4.8
作者：
Patwari, Parth;Chutkow, William A.;Lee, Richard T.
通讯作者：
Lee, Richard T.
影响因子：
4.8
作者：
Saxena, Geetu;Chen, Junqin;Shalev, Anath
通讯作者：
Shalev, Anath
TXNIP调节人类的外周葡萄糖代谢。
影响因子：
15.8
作者：
Parikh, Hemang;Carlsson, Emma;Chutkow, William A.;Johansson, Lovisa E.;Storgaard, Heidi;Poulsen, Pernille;Saxena, Richa;Ladd, Christine;Schulze, P. Christian;Mazzini, Michael J.;Jensen, Christine Bjorn;Krook, Anna;Bjornholm, Marie;Tornqvist, Hans;Zierath, Juleen R.;Ridderstrale, Martin;Altshuler, David;Lee, Richard T.;Vaag, Allan;Groop, Leif C.;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.
影响因子：
5
作者：
Dutta, KK;Nishinaka, Y;Toyokuni, S
通讯作者：
Toyokuni, S
影响因子：
20.1
作者：
Chen YR;Zweier JL
通讯作者：
Zweier JL