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Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon β-adrenergic insult

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Abstract

Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18), however, the process of inflammation cascades has not been fully illustrated. The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation. With bioinformatics analysis, galectin-3 was identified as a potential key downstream effector of β-AR and IL-18 activation. The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain. In the heart of mice treated with β-AR agonist isoproterenol (ISO, 5 mg kg−1), galectin-3 expression was upregulated markedly later than IL-18 activation, and Nlrp3−/− and Il18−/− mice did not show ISO-induced galectin-3 upregulation. It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment. Moreover, galectin-3 deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase. Treatment with a galectin-3 inhibitor, but not a β-blocker, one day after ISO treatment effectively attenuated cardiac inflammation and injury. In conclusion, galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute β-AR activation, a galectin-3 inhibitor effectively blocks cardiac injury one day after β-AR insult.

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Data and materials availability statement

All data associated with this study are present in the paper or the Supplementary Materials. Any other relevant data are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2021YFF0501401), the National Natural Science Foundation of China (82030072), the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research (BMU2019JI007), the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (81830009, 81822003), the Beijing Municipal Natural Science Foundation (7191013), the Key Clinical Projects of Peking University Third Hospital (BYSYZD2019022), and CAMS Innovation Fund for Medical Sciences to (2021-I2M-5-003). We thank Dr. Hao Dong and Dr. Nan Li from Peking University for their help on the statistical analysis of clinical data.

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Authors and Affiliations

  1. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China

    Guomin Hu, Jimin Wu, Huijun Gu, Xiangning Deng, Wenli Xu, Shan Feng, Shuaixing Wang, Yao Song, Xinyu Wang, Youyi Zhang, Han Xiao & Erdan Dong

  2. NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, 100191, China

    Guomin Hu, Jimin Wu, Huijun Gu, Xiangning Deng, Wenli Xu, Shan Feng, Shuaixing Wang, Yao Song, Xinyu Wang, Youyi Zhang, Han Xiao & Erdan Dong

  3. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China

    Guomin Hu, Jimin Wu, Huijun Gu, Xiangning Deng, Wenli Xu, Shan Feng, Shuaixing Wang, Yao Song, Xinyu Wang, Youyi Zhang, Han Xiao & Erdan Dong

  4. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China

    Guomin Hu, Jimin Wu, Huijun Gu, Xiangning Deng, Wenli Xu, Shan Feng, Shuaixing Wang, Yao Song, Xinyu Wang, Youyi Zhang, Han Xiao & Erdan Dong

  5. Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, 100191, China

    Guomin Hu, Jimin Wu, Huijun Gu, Xiangning Deng, Wenli Xu, Shan Feng, Shuaixing Wang, Yao Song, Xinyu Wang, Youyi Zhang, Han Xiao & Erdan Dong

  6. Department of Physiology and Pathophysiology, Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Zhengda Pang & Xiuling Deng

  7. Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA

    Aleksandr E. Vendrov, Nageswara R. Madamanchi & Marschall S. Runge

  8. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100087, China

    Huijun Gu

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  1. Guomin Hu
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  2. Jimin Wu
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  17. Erdan Dong
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Correspondence to Han Xiao.

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Dr. Marschall Runge is a member of the Board of Directors at Eli Lilly and Company. The other authors declare no conflict of interest.

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Hu, G., Wu, J., Gu, H. et al. Galectin-3-centered paracrine network mediates cardiac inflammation and fibrosis upon β-adrenergic insult. Sci. China Life Sci. 66, 1067–1078 (2023). https://doi.org/10.1007/s11427-022-2189-x

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