Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis.
Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis.
复制标题
阿托伐他汀通过调节 Nrf2-xCT/GPx4 轴诱导线粒体依赖性铁死亡。
DOI：
10.3389/fcell.2022.806081
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发表时间：
2022
影响因子：
5.5
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Zhang Q;Qu H;Chen Y;Luo X;Chen C;Xiao B;Ding X;Zhao P;Lu Y;Chen AF;Yu Y
他汀类药物作为临床心血管疾病治疗的基石之一，应用范围广泛。然而，常用的他汀类药物有副作用，特别是肌肉相关症状（SAMS），如肌无力，疼痛，痉挛和横纹肌溶解的严重情况。这种不良的肌肉效应是他汀类药物不依从和/或停药的主要原因之一，导致不良心血管结局。此外，肌细胞损伤的潜在机制仍不清楚。在这里，我们发现，铁凋亡，程序性铁依赖性细胞死亡，作为他汀类药物诱导的肌病的机制。在阿托伐他汀、洛伐他汀、瑞舒伐他汀和普伐他汀四种候选药物中，只有阿托伐他汀可以导致人心肌细胞（HCM）和小鼠骨骼肌细胞（C2 C12）的铁细胞凋亡，而不是人脐静脉内皮细胞（HUVEC）。阿托伐他汀以剂量依赖性方式抑制HCM和C2 C12细胞活力，伴随着细胞内铁离子、活性氧（ROS）和脂质过氧化的显著增加。一项值得注意的研究发现，这些改变特别发生在线粒体中，并导致线粒体功能障碍。阿托伐他汀干预期间心肌损伤的生物标志物显著增加。然而，所有上述增强可以被铁凋亡抑制剂抑制。从机制上讲，GSH耗竭和核因子红细胞2相关因子2（Nrf 2）、谷胱甘肽过氧化物酶4（GPx 4）和xCT胱氨酸-谷氨酸反向转运蛋白（主要成分是SLC 7A 11）的减少参与了阿托伐他汀诱导的肌细胞铁凋亡和损伤。结论：本研究揭示了阿托伐他汀诱导的肌病的病理生理机制，提示靶向铁凋亡可作为临床应用的保护性策略。
As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
2.2
作者：
Ghosh, Sharmila;Serafini, Rosanna;Varner, Dickson D.
通讯作者：
Varner, Dickson D.
影响因子：
6.1
作者：
Bonifacio, Annalisa;Mullen, Peter J.;Kraehenbuehl, Stephan
通讯作者：
Kraehenbuehl, Stephan
影响因子：
6.6
作者：
Jones, Julia M.;Player, Darren J.;Mudera, Vivek
通讯作者：
Mudera, Vivek
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei