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Semaglutide ameliorates obesity-induced cardiac inflammation and oxidative stress mediated via reduction of neutrophil Cxcl2, S100a8, and S100a9 expression

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Abstract

Obesity, which is driven by inflammation and oxidative stress, is a risk factor for cardiovascular disease. Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic drug with major effects on weight loss. In this study, single-cell transcriptomics was used to examine non-cardiomyocytes to uncover the mechanism of obesity-induced myocardial damage and the cardioprotective impact of semaglutide. We constructed obese mouse models and measured Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Reactive Oxygen Species (ROS), and Malonic dialdehyde (MDA) levels in serum and heart tissue to determine the levels of inflammation and oxidative stress in obesity and the effect of semaglutide on these levels. Then, utilizing single-cell transcriptomes to screen for key cell populations and differentially expressed genes (DEGs), we assessed the effects of obesity and semaglutide on non-cardiac cells. Finally, a DEG localization analysis was performed to explore DEGs as well as cell types associated with inflammation and oxidative stress. Semaglutide reduced increased TNF-α, IL-6, ROS, and MDA levels in serum and cardiac tissues in obese mouse. Several genes are closely associated with inflammation and oxidative stress. Chemokine (C-X-C motif) ligand 2 (Cxcl2), S100 calcium binding protein A8 (S100a8), and S100 calcium binding protein A9 (S100a9), which were elevated in obesity but decreased following semaglutide treatment, were also expressed particularly in neutrophils. Finally, by decreasing neutrophil Cxcl2, S100a8, and S100a9 expressions, semaglutide may help to reduce cardiac inflammation and oxidative stress. Semaglutide significantly reduced body weight in obese mice as well as exerted anti-inflammatory and antioxidant effects possibly by inhibiting the expression of S100a8, S100a9, and Cxcl2 in neutrophils. These discoveries are expected to reveal new molecular mechanisms underlying obesity-related heart damage and semaglutide's cardioprotective properties.

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Data availability

Data supporting the results of this study are available upon reasonable request from the first author.

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Funding

This study was supported by the Hebei Province Natural Science Foundation (H2022307026).

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Authors and Affiliations

  1. Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China

    **aoyu Pan, Shuqi Wang & Shuchun Chen

  2. Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China

    **aoyu Pan, Lin Yang, Shuqi Wang, Yanhui Liu & Shuchun Chen

  3. Department of Endocrinology, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China

    Lin Yue

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by XP, LY, LY, SW and YL The first draft of the manuscript was written by XP Writing (review and editing) was performed by SC; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shuchun Chen.

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All authors declare that there is no conflict of interests in this study.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hebei General Hospital (Date March 11, 2022/No. 202285).

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Pan, X., Yang, L., Wang, S. et al. Semaglutide ameliorates obesity-induced cardiac inflammation and oxidative stress mediated via reduction of neutrophil Cxcl2, S100a8, and S100a9 expression. Mol Cell Biochem 479, 1133–1147 (2024). https://doi.org/10.1007/s11010-023-04784-2

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