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LPS-aggravated Ferroptosis via Disrupting Circadian Rhythm by Bmal1/AKT/p53 in Sepsis-Induced Myocardial Injury

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Abstract

Circadian disruption is involved in the progress of sepsis-induced cardiomyopathy (SICM), one of the leading causes of death in sepsis. The molecular mechanism remains ambiguous. In this study, LPS was used to build SICM model in H9c2 cell. The results suggested that LPS induced cytotoxicity via increasing ferroptosis over the time of course. After screening the expressions of six circadian genes, the circadian swing of Bmal1 was dramatically restrained by LPS in H9c2 cell of SIMC vitro model. PcDNA and siRNA were used to upregulate and downregulate Bmal1 and confirmed that Bmal1 inhibited LPS-triggered ferroptosis in H9c2 cells. Then, the results suggested that AKT/p53 pathway was restrained by LPS in H9c2 cell. Rescue test indicated that Bmal1 inhibited LPS-triggered ferroptosis via AKT/p53 pathway in H9c2 cells. In summary, our findings demonstrated that LPS induced cytotoxicity via increasing ferroptosis over the time of course in H9c2 cells and Bmal1 inhibited this toxicity of LPS via AKT/p53 pathway. Although further studies are needed, our findings may contribute to a new insight to mechanism of SICM.

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Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank all of the participants for their time and effort.

Funding

This study was supported by the National Natural Science Foundation of China (grant nos. 81, 700, 243) and the subject of Jiangsu Province Hospital of Chinese Medicine (grant no. Y2020CX42).

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Authors and Affiliations

  1. Department of Emergency, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu Province, China

    Hao Lin, Kong-qin Lin, Yu-tao Zhu & Wen Yang

  2. Department of Intensive Care Unit, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu Province, China

    Fang Ji & Long-hai Zhang

  3. Department of Neurology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu Province, China

    Jian-gao Zhao

  4. Department of Intensive Care Unit, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China

    Ying-hao Pei

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  1. Hao Lin
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Contributions

LH, JF, and LKQ: conceptualization. LH, JF, LKQ, ZYT, YW, and ZLH: methodology and investigation. PYH: writing–review and editing. ZJG and PYH: supervision and project administration.

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Correspondence to Jian-gao Zhao or Ying-hao Pei.

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Hao Lin, Fang Ji, and Kong-qin Lin contributed equally to this work and share first authorship.

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Lin, H., Ji, F., Lin, Kq. et al. LPS-aggravated Ferroptosis via Disrupting Circadian Rhythm by Bmal1/AKT/p53 in Sepsis-Induced Myocardial Injury. Inflammation 46, 1133–1143 (2023). https://doi.org/10.1007/s10753-023-01804-7

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