Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure  

作　　者：Jin-fu Qian Shi-qi Liang Qin-yan Wang Jia-chen Xu Wu Luo Wei-jian Huang Gao-jun Wu Guang Liang 

机构地区：[1]Department of Cardiology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325035,China [2]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China [3]Medical Research Center,the First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325035,China

出　　处：《Acta Pharmacologica Sinica》2024年第3期531-544,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82271347 to GJW);Wenzhou City Research Project(ZY2020016 to GJW).

摘　　要：Cardiac inflammation contributes to heart failure(HF)induced by isoproterenol(ISO)through activatingβ-adrenergic receptors(β-AR).Recent evidence shows that myeloid differentiation factor 2(MD2),a key protein in endotoxin-induced inflammation,mediates inflammatory heart diseases.In this study,we investigated the role of MD2 in ISO-β-AR-induced heart injuries and HF.Mice were infused with ISO(30 mg·kg^(−1)·d^(−1))via osmotic mini-pumps for 2 weeks.We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice.Either MD2 knockout or administration of MD2 inhibitor L6H21(10 mg/kg every 2 days,i.g.)could prevent mouse hearts from ISO-induced inflammation,remodelling and dysfunction.Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries.In ISO-treated H9c2 cardiomyocyte-like cells,neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages,MD2 knockout or pre-treatment with L6H21(10μM)alleviated ISO-induced inflammatory responses,and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts.We demonstrated that ISO induced MD2 activation in cardiomyocytes viaβ1-AR-cAMP-PKA-ROS signalling axis,and induced inflammatory responses in macrophages viaβ2-AR-cAMP-PKA-ROS axis.This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

关 键 词：heart failure ISOPROTERENOL inflammation MD2 CARDIOMYOCYTES MACROPHAGES 

分 类 号：R96[医药卫生—药理学]