Ferroptosis as a target for protection against cardiomyopathy

By X. Fang, Hao Wang, Dan Han, Enjun Xie, Xiang Yang, Jiayu Wei, Shanshan Gu, F. Gao, N. Zhu, Xiangju Yin and 10 more. Proceedings of the National Academy of Sciences of the United States of America, 2019

1,832 citations recorded by the source corpus.

Significance Nonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined iron-dependent cell death, mediates both chemotherapy- and ischemia/reperfusion-induced cardiomyopathy. RNA-sequencing analysis revealed up-regulation of heme oxygenase 1 by doxorubicin as a major mechanism of ferroptotic cardiomyopathy. As a result, heme oxygenase 1 degrades heme and releases free iron in cardiomyocytes, which in turn leads to generation of oxidized lipids in the mitochondria membrane. Most importantly, both iron chelation therapy and pharmacologically blocking ferroptosis could significantly alleviate cardiomyopathy in mice. These findings suggest targeting ferroptosis as a strategy for treating deadly heart disease. 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 up-regulation 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. Mitochondria-targeted 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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/5465ec6fbc4c4035819ea9497391e0b1a5fae063

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Brent R. Stockwell
2. Xuejun Jiang
3. Yongsheng Li
4. Dingshan Li
5. Qing-zhang Tuo
6. P. Lei
7. W. Gu
8. R. Kang

In Pulmonary and Respiratory Medicine

1. Brent R. Stockwell
2. Xuejun Jiang
3. Qing-zhang Tuo
4. P. Lei
5. W. Gu
6. Yongsheng Li
7. Dingshan Li
8. Furong Zeng

Citations in the corpus

• Ferroptosis: mechanisms and links with diseases (2021, background): “In DOX-treated murine hearts, HO-1 was significantly upregulated, promoting systemic accumulation of nonheme iron via heme degradation and accompanied by lipid peroxidation and ferroptosis.280 Ferrostatin-1 can significantly reduce DOX cardiomyopathy.280 And ferrostatin-1 also has been shown to amel”
• The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “Firstly, the mitochondria in ferroptotic cells are small and mitochondria-targeted antioxidants can inhibit ferroptosis, indicating a correlation of mitochondria with ferroptosis.(4,10,26) Mitochondria play an important role in cysteine deprivationinduced ferroptosis.”
• Emerging mechanisms and disease relevance of ferroptosis (2020, result): “This conclusion was confirmed by a more recent in vivo study [78].”
• Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020, neutral): “Although some studies demonstrated that iron chelation using DXZ ameliorated DIC in a mouse model (5, 42), we speculate that long-term treatment with DXZ in vivo might be effective for DIC, possibly irrespective of ferroptosis.”
• Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, positive): “Inhibition of ferroptosis through using ferrostatin-1 and HO-1 antagonist exerts some protective effect against myocardial injury [329].”