Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis

被引:41
作者
Ji, Qing-Xin [1 ,2 ]
Zeng, Fei-Yan [3 ]
Zhou, Jian [4 ]
Wu, Wen-Bin [1 ]
Wang, Xu-Jie [1 ,2 ]
Zhang, Zhen [1 ,2 ]
Zhang, Guo-Yan [1 ,2 ]
Tong, Jie [1 ,2 ]
Sun, Di-Yang [1 ]
Zhang, Jia-Bao [1 ]
Cao, Wen-Xiang [1 ]
Shen, Fu-Ming [2 ]
Lu, Jin-Jian [5 ]
Li, Dong-Jie [2 ,6 ]
Wang, Pei [1 ]
机构
[1] Naval Med Univ, Mil Med Univ 2, Sch Pharm, Dept Pharmacol, Shanghai, Peoples R China
[2] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Cardiac Surg, Shanghai, Peoples R China
[3] Tongji Univ, Sch Med, Shanghai Peoples Hosp 4, Dept Pharmacol, Shanghai, Peoples R China
[4] Tongji Univ Sch Med, Shanghai Peoples Hosp 10, Dept Cardiac Surg, Shanghai, Peoples R China
[5] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Peoples R China
[6] Tongji Univ, Sch Med, Inst Nucl Med, Shanghai, Peoples R China
关键词
OXIDATIVE STRESS; APOPTOSIS; RECEPTOR; GROWTH; INHIBITION; DEATH; MOTOR; GPX4;
D O I
10.1038/s41418-022-01099-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bis(N4)-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.
引用
收藏
页码:457 / 474
页数:18
相关论文
共 69 条
[1]   Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice [J].
Angeli, Jose Pedro Friedmann ;
Schneider, Manuela ;
Proneth, Bettina ;
Tyurina, Yulia Y. ;
Tyurin, Vladimir A. ;
Hammond, Victoria J. ;
Herbach, Nadja ;
Aichler, Michaela ;
Walch, Axel ;
Eggenhofer, Elke ;
Basavarajappa, Devaraj ;
Radmark, Olof ;
Kobayashi, Sho ;
Seibt, Tobias ;
Beck, Heike ;
Neff, Frauke ;
Esposito, Irene ;
Wanke, Ruediger ;
Foerster, Heidi ;
Yefremova, Olena ;
Heinrichmeyer, Marc ;
Bornkamm, Georg W. ;
Geissler, Edward K. ;
Thomas, Stephen B. ;
Stockwell, Brent R. ;
O'Donnell, Valerie B. ;
Kagan, Valerian E. ;
Schick, Joel A. ;
Conrad, Marcus .
NATURE CELL BIOLOGY, 2014, 16 (12) :1180-U120
[2]   Empowerment of 15-Lipoxygenase Catalytic Competence in Selective Oxidation of Membrane ETE-PE to Ferroptotic Death Signals, HpETE-PE [J].
Anthonymuthu, Tamil S. ;
Kenny, Elizabeth M. ;
Shrivastava, Indira ;
Tyurina, Yulia Y. ;
Hier, Zachary E. ;
Ting, Hsiu-Chi ;
Dar, Haider H. ;
Tyurin, Vladimir A. ;
Nesterova, Anastasia ;
Amoscato, Andrew A. ;
Mikulska-Ruminska, Karolina ;
Rosenbaum, Joel C. ;
Mao, Gaowei ;
Zhao, Jinming ;
Conrad, Marcus ;
Kellum, John A. ;
Wenzel, Sally E. ;
VanDemark, Andrew P. ;
Bahar, Ivet ;
Kagan, Valerian E. ;
Bayir, Hulya .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2018, 140 (51) :17835-17839
[3]   Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease [J].
Bao, Wen-Dai ;
Pang, Pei ;
Zhou, Xiao-Ting ;
Hu, Fan ;
Xiong, Wan ;
Chen, Kai ;
Wang, Jing ;
Wang, Fudi ;
Xie, Dong ;
Hu, Ya-Zhuo ;
Han, Zhi-Tao ;
Zhang, Hong-Hong ;
Wang, Wang-Xia ;
Nelson, Peter T. ;
Chen, Jian-Guo ;
Lu, Youming ;
Man, Heng-Ye ;
Liu, Dan ;
Zhu, Ling-Qiang .
CELL DEATH AND DIFFERENTIATION, 2021, 28 (05) :1548-1562
[4]   The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis [J].
Bersuker, Kirill ;
Hendricks, Joseph M. ;
Li, Zhipeng ;
Magtanong, Leslie ;
Ford, Breanna ;
Tang, Peter H. ;
Roberts, Melissa A. ;
Tong, Bingqi ;
Maimone, Thomas J. ;
Zoncu, Roberto ;
Bassik, Michael C. ;
Nomura, Daniel K. ;
Dixon, Scott J. ;
Olzmann, James A. .
NATURE, 2019, 575 (7784) :688-+
[5]   Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm [J].
Branchetti, Emanuela ;
Poggio, Paolo ;
Sainger, Rachana ;
Shang, Eric ;
Grau, Juan B. ;
Jackson, Benjamin M. ;
Lai, Eric K. ;
Parmacek, Michael S. ;
Gorman, Robert C. ;
Gorman, Joseph H. ;
Bavaria, Joseph E. ;
Ferrari, Giovanni .
CARDIOVASCULAR RESEARCH, 2013, 100 (02) :316-324
[6]   Control of mitochondrial function and cell growth by the atypical cadherin Fat1 [J].
Cao, Longyue L. ;
Riascos-Bernal, Dario F. ;
Chinnasamy, Prameladevi ;
Dunaway, Charlene M. ;
Hou, Rong ;
Pujato, Mario A. ;
O'Rourke, Brian P. ;
Miskolci, Veronika ;
Gou, Liang ;
Hodgson, Louis ;
Fiser, Andras ;
Sibinga, Nicholas E. S. .
NATURE, 2016, 539 (7630) :575-+
[7]   iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4 [J].
Chen, Delin ;
Chu, Bo ;
Yang, Xin ;
Liu, Zhaoqi ;
Jin, Ying ;
Kon, Ning ;
Rabadan, Raul ;
Jiang, Xuejun ;
Stockwell, Brent R. ;
Gu, Wei .
NATURE COMMUNICATIONS, 2021, 12 (01)
[8]   Organelle-specific regulation of ferroptosis [J].
Chen, Xin ;
Kang, Rui ;
Kroemer, Guido ;
Tang, Daolin .
CELL DEATH AND DIFFERENTIATION, 2021, 28 (10) :2843-2856
[9]   Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability [J].
Chi, Chen ;
Fu, Hui ;
Li, Yong-Hua ;
Zhang, Guo-Yan ;
Zeng, Fei-Yan ;
Ji, Qing-Xin ;
Shen, Qi-Rui ;
Wang, Xu-Jie ;
Li, Zi-Chen ;
Zhou, Can-Can ;
Sun, Di-Yang ;
Fu, Jiang-Tao ;
Wu, Wen-Bin ;
Zhang, Ping-Ping ;
Zhang, Jia-Bao ;
Liu, Jian ;
Shen, Fu-Ming ;
Li, Dong-Jie ;
Wang, Pei .
EUROPEAN HEART JOURNAL, 2022, 43 (43) :4579-+
[10]   12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases [J].
Conrad, Marcus ;
Sandin, Asa ;
Foerster, Heidi ;
Seiler, Alexander ;
Frijhoff, Jeroen ;
Dagnell, Markus ;
Bornkamm, Georg W. ;
Radmark, Olof ;
van Huijsduijnen, Rob Hooft ;
Aspenstrom, Pontus ;
Boehmer, Frank ;
Ostman, Arne .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (36) :15774-15779