Ferroptosis as a target for protection against cardiomyopathy

被引:1699
作者
Fang, Xuexian [1 ]
Wang, Hao [1 ,2 ]
Han, Dan [1 ]
Xie, Enjun [1 ]
Yang, Xiang [1 ]
Wei, Jiayu [1 ]
Gu, Shanshan [3 ,4 ,5 ]
Gao, Feng [6 ]
Zhu, Nali [7 ,8 ,9 ]
Yin, Xiangju [1 ]
Cheng, Qi [1 ]
Zhang, Pan [1 ]
Dai, Wei [1 ]
Chen, Jinghai [6 ]
Yang, Fuquan [7 ,8 ,9 ]
Yang, Huang-Tian [3 ,4 ,5 ]
Linkermann, Andreas [10 ]
Gu, Wei [11 ,12 ]
Min, Junxia [1 ]
Wang, Fudi [1 ,2 ]
机构
[1] Zhejiang Univ, Inst Translat Med, Sch Publ Hlth, Sch Med,Affiliated Hosp 1, Hangzhou 310058, Zhejiang, Peoples R China
[2] Zhengzhou Univ, Sch Publ Hlth, Precis Nutr Innovat Ctr, Dept Nutr, Zhengzhou 450001, Henan, Peoples R China
[3] Shanghai Jiao Tong Univ, Inst Hlth Sci, Key Lab Stem Cell Biol, Sch Med, Shanghai 200031, Peoples R China
[4] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
[5] Shanghai Jiao Tong Univ, Inst Hlth Sci, Lab Mol Cardiol, Sch Med, Shanghai 200031, Peoples R China
[6] Zhejiang Univ, Inst Translat Med, Affiliated Hosp 2, Sch Med, Hangzhou 310020, Zhejiang, Peoples R China
[7] Chinese Acad Sci, Inst Biophys, Lab Prot & Peptide Pharmaceut, Beijing 100101, Peoples R China
[8] Univ Chinese Acad Sci, Beijing 100101, Peoples R China
[9] Chinese Acad Sci, Inst Biophys, Lab Prote, Beijing 100101, Peoples R China
[10] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Med Clin 3, Dept Nephrol, D-01307 Dresden, Germany
[11] Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Inst Canc Genet, New York, NY 10032 USA
[12] Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA
基金
中国国家自然科学基金;
关键词
ferroptosis; iron; heart injury; cell death; mitochondria; CELL-DEATH; DOXORUBICIN CARDIOTOXICITY; TRANSCRIPTION FACTOR; HEART-FAILURE; DISEASE; ANTIOXIDANT; MECHANISMS; ISCHEMIA; NRF2; MITOCHONDRIA;
D O I
10.1073/pnas.1821022116
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3(-/-), Mlkl(-/-), or Fadd(-/-)Mlkl(-/-) mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated upregulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondriatargeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.
引用
收藏
页码:2672 / 2680
页数:9
相关论文
共 50 条
[1]   Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury [J].
Adlam, VJ ;
Harrison, JC ;
Porteous, CM ;
James, AM ;
Smith, RAJ ;
Murphy, MP ;
Sammut, IA .
FASEB JOURNAL, 2005, 19 (09) :1088-1095
[2]   Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene [J].
Alam, J ;
Stewart, D ;
Touchard, C ;
Boinapally, S ;
Choi, AMK ;
Cook, JL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (37) :26071-26078
[3]   Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice [J].
Allwood, Melissa A. ;
Kinobe, Robert T. ;
Ballantyne, Laurel ;
Romanova, Nadya ;
Melo, Luis G. ;
Ward, Christopher A. ;
Brunt, Keith R. ;
Simpson, Jeremy A. .
CARDIOVASCULAR PATHOLOGY, 2014, 23 (04) :231-237
[4]   Ferroptosis Inhibition: Mechanisms and Opportunities [J].
Angeli, Jose Pedro Friedmann ;
Shah, Ron ;
Pratt, Derek A. ;
Conrad, Marcus .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2017, 38 (05) :489-498
[5]  
Arola OJ, 2000, CANCER RES, V60, P1789
[6]   Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol [J].
Atzori, L ;
Chua, F ;
Dunsmore, SE ;
Willis, D ;
Barbarisi, M ;
McAnulty, RJ ;
Laurent, GJ .
THORAX, 2004, 59 (03) :217-223
[7]   HEME OXYGENASES IN CARDIOVASCULAR HEALTH AND DISEASE [J].
Ayer, Anita ;
Zarjou, Abolfazl ;
Agarwal, Anupam ;
Stocker, Roland .
PHYSIOLOGICAL REVIEWS, 2016, 96 (04) :1449-1508
[8]   Cardiac Mitochondria and Reactive Oxygen Species Generation [J].
Chen, Yeong-Renn ;
Zweier, Jay L. .
CIRCULATION RESEARCH, 2014, 114 (03) :524-537
[9]   Regulated necrosis: disease relevance and therapeutic opportunities [J].
Conrad, Marcus ;
Angeli, Jose Pedro Friedmann ;
Vandenabeele, Peter ;
Stockwell, Brent R. .
NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (05) :348-366
[10]   Resistance to hyperoxia with heme oxygenase-1 disruption: Role of iron [J].
Dennery, PA ;
Visner, G ;
Weng, YH ;
Nguyen, X ;
Lu, FH ;
Zander, D ;
Yang, GA .
FREE RADICAL BIOLOGY AND MEDICINE, 2003, 34 (01) :124-133