Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts.
Autophagy Controls Nrf2-Mediated Dichotomy in Pressure Overloaded Hearts.
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DOI：
10.3389/fphys.2021.673145
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发表时间：
2021
影响因子：
4
通讯作者：
Cui T
中科院分区：
文献类型：
--
作者：
Wu W;Qin Q;Ding Y;Zang H;Li DS;Nagarkatti M;Nagarkatti P;Wang W;Wang X;Cui T
新兴的证据表明，正常的自噬是核因子红细胞2相关因子（Nrf 2）介导的心脏保护所必需的，而自噬抑制在压力超负荷（PO）的设置中打开Nrf 2介导的心肌损伤和功能障碍。然而，这样的概念仍然需要通过仔细的体内遗传询问来充分建立。本研究旨在使用PO诱导的心肌病和心力衰竭的小鼠模型验证这一假设，其中心脏自噬和/或Nrf 2活性受到遗传抑制。在成年小鼠中，通过心肌细胞限制性（CR）敲除（KO）自噬相关（Atg）5（CR-Atg 5 KO）诱导心肌自噬抑制。CR-Atg 5 KO损害心脏适应性，同时在PO的情况下加剧心脏适应不良反应。值得注意的是，它还关闭了Nrf 2介导的防御，同时开启了PO心脏中Nrf 2操作的组织损伤。此外，心脏自噬抑制选择性地灭活细胞外信号调节激酶（ERK），这与PO心脏中心肌细胞中Nrf 2的核积聚增加和活化ERK的核转位减少相一致。机制研究表明，自噬是ERK激活所必需的，ERK抑制心肌细胞中Nrf 2驱动的血管紧张素原表达。总之，这些结果提供了直接的证据，巩固了这样的概念，即正常的自噬使Nrf 2操作的适应，同时关闭Nrf 2介导的适应不良反应，在PO心脏部分通过抑制Nrf 2驱动的血管紧张素原在心肌细胞中的表达。
Burgeoning evidence has indicated that normal autophagy is required for nuclear factor erythroid 2-related factor (Nrf2)-mediated cardiac protection whereas autophagy inhibition turns on Nrf2-mediated myocardial damage and dysfunction in a setting of pressure overload (PO). However, such a concept remains to be fully established by a careful genetic interrogation in vivo. This study was designed to validate the hypothesis using a mouse model of PO-induced cardiomyopathy and heart failure, in which cardiac autophagy and/or Nrf2 activity are genetically inhibited. Myocardial autophagy inhibition was induced by cardiomyocyte-restricted (CR) knockout (KO) of autophagy related (Atg) 5 (CR-Atg5KO) in adult mice. CR-Atg5KO impaired cardiac adaptations while exacerbating cardiac maladaptive responses in the setting of PO. Notably, it also turned off Nrf2-mediated defense while switching on Nrf2-operated tissue damage in PO hearts. In addition, cardiac autophagy inhibition selectively inactivated extracellular signal regulated kinase (ERK), which coincided with increased nuclear accumulation of Nrf2 and decreased nuclear translocation of activated ERK in cardiomyocytes in PO hearts. Mechanistic investigation revealed that autophagy is required for the activation of ERK, which suppresses Nrf2-driven expression of angiotensinogen in cardiomyocytes. Taken together, these results provide direct evidence consolidating the notion that normal autophagy enables Nrf2-operated adaptation while switching off Nrf2-mediated maladaptive responses in PO hearts partly through suppressing Nrf2-driven angiotensinogen expression in cardiomyocytes.
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影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
Nrf2 缺乏会加剧阿霉素引起的心脏毒性和心脏功能障碍
影响因子：
--
作者：
Li S;Wang W;Niu T;Wang H;Li B;Shao L;Lai Y;Li H;Janicki JS;Wang XL;Tang D;Cui T
通讯作者：
Cui T
影响因子：
6
作者：
Al-Sawaf, Othman;Clarner, Tim;Wruck, Christoph Jan
通讯作者：
Wruck, Christoph Jan
DOI：
10.1161/atvbaha.109.189480
发表时间：
2009-11-01
影响因子：
8.7
作者：
Li, Jinqing;Ichikawa, Tomonaga;Cui, Taixing
通讯作者：
Cui, Taixing
影响因子：
5.8
作者：
Bryan, Holly K.;Olayanju, Adedamola;Park, B. Kevin
通讯作者：
Park, B. Kevin