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SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis

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Abstract

Purpose

Systemic hypertension may induce adverse hypertrophy of the left cardiac ventricle. Pathological cardiac hypertrophy is a common cause of heart failure. We investigated the significance of ferroptosis repressor xCT in hypertrophic cardiomyopathy.

Methods

xCT expression in angiotensin II (Ang II)-treated mouse hearts and rat cardiomyocytes was determined using qRT-PCR and Western blotting. Cardiac hypertrophy was induced by Ang II infusion in xCT knockout mice and their wildtype counterparts. Blood pressure, cardiac pump function, and pathological changes of cardiac remodeling were analyzed in these mice. Cell death, oxidative stress, and xCT-mediated ferroptosis were examined in Ang II-treated rat cardiomyocytes.

Results

After Ang II infusion, xCT was downregulated at day 1 but upregulated at day 14 at both mRNA and protein levels. It was also decreased in Ang II-treated cardiomyocytes, but not in cardiofibroblasts. Inhibition of xCT exacerbated cardiomyocyte hypertrophy and boosted the levels of ferroptosis biomarkers Ptgs2, malondialdehyde, and reactive oxygen species induced by Ang II, while overexpression of xCT opposed these detrimental effects. Furthermore, knockout of xCT aggravated Ang II-mediated mouse cardiac fibrosis, hypertrophy, and dysfunction. Ferrostatin-1, a ferroptosis inhibitor, alleviated the exacerbation of cardiomyocyte hypertrophy caused by inhibiting xCT in cultured rat cells or ablating xCT in mice.

Conclusion

xCT acts as a suppressor in Ang II-mediated cardiac hypertrophy by blocking ferroptosis. Positive modulation of xCT may therefore represent a novel therapeutic approach against cardiac hypertrophic diseases.

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Data Availability

All data involved in this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (81670380, 81770466), the CAMS Initiative for Innovative Medicine at Chinese Academy of Medical Sciences (2017-I2M-1-008), the State Key Laboratory Special Fund 2060204, and the National Key R&D Program of China (2017YFC1308000).

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Authors and Affiliations

  1. Department of Pathology, Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China

    Xiyu Zhang, Cuiting Zheng, Zhenqiang Gao & Yan Meng

  2. State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Hongyu Chen, Kai Li & Hongbing Zhang

  3. Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China

    Lingling Wang

  4. Department of Pharmacology, Capital Medical University, Beijing, China

    Yuanyuan Zheng

  5. Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China

    Chunjia Li

  6. Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Beijing Aortic Disease Center, Beijing Laboratory for Cardiovascular Precision Medicine, and Beijing Engineering Research Center of Vascular Prostheses, Capital Medical University, Beijing, China

    Hongjia Zhang & Ming Gong

Authors
  1. Xiyu Zhang
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  2. Cuiting Zheng
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  9. Hongjia Zhang
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  10. Ming Gong
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  11. Hongbing Zhang
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  12. Yan Meng
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Contributions

Xiyu Zhang and Cuiting Zheng contributed to the collection of data, data analysis and interpretation, and article writing; Zhenqiang Gao, Hongyu Chen, Kai Li, Lingling Wang, Chunjia Li, and Yuanyuan Zheng contributed to the collection of data, as well as data analysis and interpretation; Hongjia Zhang and Ming Gong provided financial support; Hongbing Zhang and Yan Meng provided financial support and contributed to conception and design, and manuscript writing. Yan Meng provided administrative support and final approval of the manuscript.

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Correspondence to Hongbing Zhang or Yan Meng.

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Zhang, X., Zheng, C., Gao, Z. et al. SLC7A11/xCT Prevents Cardiac Hypertrophy by Inhibiting Ferroptosis. Cardiovasc Drugs Ther 36, 437–447 (2022). https://doi.org/10.1007/s10557-021-07220-z

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