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Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis

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Abstract

Septic cardiomyopathy is a severe cardiovascular disease with a poor prognosis. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to improve ischemia–reperfusion injury by alleviating ferroptosis in cardiomyocyte. However, the role of dapagliflozin in sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced septic cardiomyopathy. Our results indicate that dapagliflozin improved cardiac function in septic cardiomyopathy experimental mice. Mechanistically, dapagliflozin works by inhibiting the translation of key proteins involved in ferroptosis, such as GPX4, FTH1, and SLC7A11. It also reduces the transcription of lipid peroxidation-related mRNAs, including PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1.

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Funding

This study was supported by the National Natural Science Foundation of China (92068116 and 82370305) and the Jiangsu Distinguished Young Scholars Fund (Approval No: BK20211501); the Funds for Distinguished Young Scientists in Nanjing (JQX22001); China Postdoctoral Science Foundation (2023M731631); Nanjing Postdoctoral Science Foundation for Jinxuan Zhao and Jiangsu “Mass Innovation and Entrepreneurship” Talent Program to Jinxuan Zhao; Anhui Medical University Research Enhancement Program Funding Project(2023xkjT029); Anhui Provincial Natural Science Research Project for Higher Education Institutions(KJ2021ZD0027) and Collaborative Project between the First Affiliated Hospital of Anhui Medical University and Hefei Zhongke Ion Medical Technology Equipment Co., Ltd.(CIM-HT-2018–327).

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Author notes

  1. Ke Hu, Jiaxin Hu and Pin Jiang contributed equally to this work.

Authors and Affiliations

  1. The Affiliated Drum Tower Hospital of Nanjing Medical University, Nanjing, 210008, Jiangsu, China

    Ke Hu & Jun Xie

  2. Department of General Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Pin Jiang

  3. Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, 445000, Hubei, China

    Jiaxin Hu

  4. Department of Cardiology, National Cardiovascular Disease Regional Center for Anhui, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Bing Song, Haiting Chen & Jun Xie

  5. Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, 210008, Jiangsu, China

    Ya Hou & Jinxuan Zhao

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  1. Ke Hu
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Contributions

JX, HC and JZ conceived and designed the study. KH, PJ, YH and JH performed the experiments. KH and PJ drafted the manuscript. BS contributed to data collection and analysis. All authors have read and approved the manuscript, and all data were generated internally.

Corresponding authors

Correspondence to Jinxuan Zhao, Haiting Chen or Jun Xie.

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The authors declare no competing interests.

Ethical approval

All procedures with animals were approved by the Institution Ethics Committee of Anhui Medical University (Anhui, China) (No. LLSC20230846) and performed in accordance with the guidelines from Directive 2010/63/EU of the European Parliament.

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Hu, K., Jiang, P., Hu, J. et al. Dapagliflozin attenuates LPS-induced myocardial injury by reducing ferroptosis. J Bioenerg Biomembr (2024). https://doi.org/10.1007/s10863-024-10020-3

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