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.