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Intermedin1–53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis

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Abstract

Intermedin (IMD), a paracrine/autocrine peptide, protects against cardiac fibrosis. However, the underlying mechanism remains poorly understood. Previous study reports that activation of nucleotide-binding oligomerization domain (NOD)–like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cardiac fibrosis. In this study, we aimed to investigate whether IMD mitigated cardiac fibrosis by inhibiting NLRP3. Cardiac fibrosis was induced by angiotensin II (Ang II) infusion for 2 weeks in rats. Western blot, real-time PCR, histological staining, immunofluorescence assay, RNA sequencing, echocardiography, and hemodynamics were used to detect the role and the mechanism of IMD in cardiac fibrosis. Ang II infusion resulted in rat cardiac fibrosis, shown as over-deposition of myocardial interstitial collagen and cardiac dysfunction. Importantly, NLRP3 activation and endoplasmic reticulum stress (ERS) were found in Ang II–treated rat myocardium. Ang II infusion decreased the expression of IMD and increased the expression of the receptor system of IMD in the fibrotic rat myocardium. IMD treatment attenuated the cardiac fibrosis and improved cardiac function. In addition, IMD inhibited the upregulation of NLRP3 markers and ERS markers induced by Ang II. In vitro, IMD knockdown by small interfering RNA significantly promoted the Ang II–induced cardiac fibroblast and NLRP3 activation. Moreover, silencing of inositol requiring enzyme 1 α (IRE1α) blocked the effects of IMD inhibiting fibroblast and NLRP3 activation. Pre-incubation with PKA pathway inhibitor H89 blocked the effects of IMD on the anti-ERS, anti-NLRP3, and anti-fibrotic response. In conclusion, IMD alleviated cardiac fibrosis by inhibiting NLRP3 inflammasome activation through suppressing IRE1α via the cAMP/PKA pathway.

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Acknowledgements

We thank Yao Song for excellent technical assistance in echocardigraphy. We thank Qiang Shen for technical assistance in H&E and Picrosirius red staining.

Funding

This research was supported by the National Natural Science Foundation of China (nos. 32071113 and 31872790) and the Beijing Natural Science Foundation (nos. 7212059).

Author information

Author notes

  1. Lin-Shuang Zhang and Jin-Sheng Zhang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China

    Lin-Shuang Zhang, Jin-Sheng Zhang, Yue-Long Hou, Wei-Wei Lu, Xian-Qiang Ni, Chao-Shu Tang & Yong-Fen Qi

  2. Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, HaidianDistrict, No. 38 Xueyuan Road, Beijing, 100083, China

    Lin-Shuang Zhang, Jin-Sheng Zhang, Wei-Wei Lu, Xian-Qiang Ni, Yan-Rong Yu, Mo-Zhi Jia & Yong-Fen Qi

  3. School of Nursing, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Lin-Shuang Zhang

  4. Department of Respiratory Disease, Peking University Third Hospital, Beijing, China

    Fan Lin

  5. Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    Xiu-Ying Liu & Xiu-Jie Wang

  6. Department of Cardiology, Fu Xing Hospital, Capital Medical University, A20 Fuxingmenwai Street, Xicheng District, Beijing, 100038, China

    Ling Han

  7. Department of Endocrinology, Peking University International Hospital, Life Park Road No. 1, Zhongguancun Life Science Park, Changping District, Beijing, 102206, China

    San-Bao Chai

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  2. Jin-Sheng Zhang
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  3. Yue-Long Hou
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  12. Ling Han
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  14. Yong-Fen Qi
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Contributions

Yong-Fen Qi, Chao-Shu Tang, and Jin-Sheng Zhang designed the study. Lin-Shuang Zhang, Jin-Sheng Zhang, Yue-Long Hou, Wei-Wei Lu, Xian-Qiang Ni, Fan Lin, and Xiu-Ying Liu performed all the experiments. Lin-Shuang Zhang and Jin-Sheng Zhang also performed the data analysis and drafted the manuscript. Yong-Fen Qi, Xiu-Jie Wang, Yan-Rong Yu, Mo-Zhi Jia, Ling Han, and San-Bao Chai critically revised the manuscript. All the authors reviewed the final manuscript.

Corresponding authors

Correspondence to Ling Han, San-Bao Chai or Yong-Fen Qi.

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Zhang, LS., Zhang, JS., Hou, YL. et al. Intermedin1–53 Inhibits NLRP3 Inflammasome Activation by Targeting IRE1α in Cardiac Fibrosis. Inflammation 45, 1568–1584 (2022). https://doi.org/10.1007/s10753-022-01642-z

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  • DOI: https://doi.org/10.1007/s10753-022-01642-z

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