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 inflammmasome 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.

Ning Cao;Jing-jing Wang;Ji-min Wu;Wen-li Xu;Rui Wang;Xian-da Chen;Ye-nan Feng;Wen-wen Cong;You-yi Zhang;Han Xiao;Er-dan Dong

Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital;NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides;Key Laboratory of Molecular Cardiovascular Science,Ministry of Education;Beijing Key Laboratory of Cardiovascular Receptors Research,Beijing 100191,China;Intensive Care Unit,Emergency Medical Research Institute,Tianjin First Center Hospital,Tianjin 300192,China;Ministry-of-Education Key Laboratory of Xinjiang Endemic and Ethnic Diseases,Department of Physiology,Shihezi University,Shihezi 832000,China

中国药理学报（英文版）

[1]Ning Cao;Jing-jing Wang;Ji-min Wu;Wen-li Xu;Rui Wang;Xian-da Chen;Ye-nan Feng;Wen-wen Cong;You-yi Zhang;Han Xiao;Er-dan Dong-.Glibenclamide alleviates β adrenergic receptor activation-induced cardiac inflammation)[J].中国药理学报（英文版）,2022(05):1243-1250

Glibenclamide,Adrenergic,inflammmasome

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