Abstract
β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by β-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the β-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of β-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates β-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.
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Acknowledgements
This work was supported by the National Key R&D Program (grant number 2020YFC2004704 to Han Xiao), UMHS-PUHSC Joint Institute for Translational and Clinical Research (grant number BMU2019JI007 to You-yi Zhang), the Natural Science Foundation of China (grant numbers 81822003 and 81670205 to Han Xiao; 81830009 to You-yi Zhang), and the Beijing Municipal Natural Science Foundation (grant number 7191013 to Er-dan Dong), and the Key Clinical Projects of Peking University Third Hospital (grant number BYSYZD2019022 to Han Xiao).
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HX, YYZ and EDD conceived the project and designed the study. NC, JJW, JMW, WLX, RW, XDC, YNF and WWC performed the experiments. NC and JJW analysed the data. NC and JMW wrote the manuscript.
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Cao, N., Wang, Jj., Wu, Jm. et al. Glibenclamide alleviates β adrenergic receptor activation-induced cardiac inflammation. Acta Pharmacol Sin 43, 1243–1250 (2022). https://doi.org/10.1038/s41401-021-00734-0
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DOI: https://doi.org/10.1038/s41401-021-00734-0
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