Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.
Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.
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Nrf1 通过调节蛋白质稳态和氧化还原平衡来促进心脏再生和修复。
DOI：
10.1038/s41467-021-25653-w
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发表时间：
2021-09-06
影响因子：
16.6
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Cui M;Atmanli A;Morales MG;Tan W;Chen K;Xiao X;Xu L;Liu N;Bassel-Duby R;Olson EN
损伤后，再生组织中的细胞具有再生能力。再生细胞适应损伤诱导的应激条件并激活再生程序的机制仍有待确定。在这里，使用哺乳动物新生儿心脏再生模型，我们表明，Nrf 1，一种应激反应性转录因子编码的核因子红细胞2样1（Nfe 2l 1）基因，被激活再生心肌细胞。Nrf 1的基因缺失阻止了再生心肌细胞激活心脏再生所需的转录程序。相反，Nrf 1过表达保护成年小鼠心脏免受缺血/再灌注（I/R）损伤。nrf 1还保护人类诱导多能干细胞衍生的心肌细胞免受阿霉素诱导的心脏毒性和其他心脏毒素的影响。Nrf 1的保护功能是由双重应激反应机制介导的，包括蛋白酶体和氧化还原平衡的激活。我们的研究结果表明，由Nrf 1介导的适应性应激反应机制是新生儿心脏再生所必需的，并在成人心脏中赋予心脏保护作用。损伤后，再生组织中的细胞可以再生，但它们如何适应损伤条件以再生组织尚不清楚。在这里，作者确定了一种对新生儿心脏再生至关重要的应激反应和心脏保护因子Nrf 1。
Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart. Following injury, cells in regenerative tissues can regrow, but how they adapt to injury conditions to regenerate the tissue is unclear. Here the authors identify a stress-responsive and cardioprotective factor Nrf1 that is critical for neonatal heart regeneration.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
20.1
作者：
Hu D;Linders A;Yamak A;Correia C;Kijlstra JD;Garakani A;Xiao L;Milan DJ;van der Meer P;Serra M;Alves PM;Domian IJ
通讯作者：
Domian IJ
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
5.9
作者：
Kijlstra JD;Hu D;Mittal N;Kausel E;van der Meer P;Garakani A;Domian IJ
通讯作者：
Domian IJ
影响因子：
82.9
作者：
Bartelt A;Widenmaier SB;Schlein C;Johann K;Goncalves RLS;Eguchi K;Fischer AW;Parlakgül G;Snyder NA;Nguyen TB;Bruns OT;Franke D;Bawendi MG;Lynes MD;Leiria LO;Tseng YH;Inouye KE;Arruda AP;Hotamisligil GS
通讯作者：
Hotamisligil GS