Glibenclamide alleviates β adrenergic receptor activation-induced cardiac inflammation  

作　　者：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 

机构地区：[1]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 [2]Intensive Care Unit,Emergency Medical Research Institute,Tianjin First Center Hospital,Tianjin,300192,China [3]Ministry-of-Education Key Laboratory of Xinjiang Endemic and Ethnic Diseases,Department of Physiology,Shihezi University,Shihezi,832000,China

出　　处：《Acta Pharmacologica Sinica》2022年第5期1243-1250,共8页中国药理学报（英文版）

基　　金：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);the Beijing Municipal Natural Science Foundation(grant number 7191013 to Er-dan Dong);the Key Clinical Projects of Peking University Third Hospital(grant number BYSYZD2019022 to Han Xiao).

摘　　要：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 byβ-AR overactivation.In the present study,male C57BL/6J mice were treated with or without theβ-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 ofβ-AR,by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes.In conclusion,glibenclamide alleviatesβ-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.

关 键 词：GLIBENCLAMIDE cardiac inflammation ISOPRENALINE sympathetic stress NLRP3 inflammasome adrenergic receptor 

分 类 号：R285.5[医药卫生—中药学]