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

doi:10.1038/s41401-023-01179-3

科研成果详情

题名	Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure
作者	Qian, Jin-fu1,2; Liang, Shi-qi1,2; Wang, Qin-yan 2; Xu, Jia-chen1,2; Luo, Wu2,3; Huang, Wei-jian1; Wu, Gao-jun1; Liang, Guang1,2
发表日期	2023-11-02
发表期刊	ACTA PHARMACOLOGICA SINICA 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access
关键词	heart failure isoproterenol inflammation MD2 cardiomyocytes macrophages
其他关键词	OXIDATIVE STRESS ; EXPRESSION ; STIMULATION ; HYPERTROPHY ; INDUCTION ; APOPTOSIS ; FIBROSIS ; TARGET ; INJURY ; CELL
摘要	Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating beta-adrenergic receptors (beta-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-beta-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg center dot kg-1 center dot 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 (10 mu M) 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 via beta 1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via beta 2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.
资助项目	This work was supported by the National Natural Science Foundation of China (82271347 to GJW) and Wenzhou City Research Project (ZY2020016 to GJW). [82271347]; National Natural Science Foundation of China [ZY2020016]; Wenzhou City Research Project
出版者	NATURE PUBL GROUP
ISSN	1671-4083
EISSN	1745-7254
卷号	45 期号:3 页码:531-544
DOI	10.1038/s41401-023-01179-3
页数	14
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS记录号	WOS:001092104600001
收录类别	SCIE ; PUBMED ; SCOPUS ; 万方 ; ISTIC ; CSCD
URL	查看原文
PubMed ID	37919475
SCOPUSEID	2-s2.0-85175530681
通讯作者地址	[Wu, Gao-jun]Department of Cardiology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China ; [Liang, Guang]Department of Cardiology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Pharmacology;Pharmacology (medical)
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/183604
专题	附属第一医院第一临床医学院（信息与工程学院）、附属第一医院药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者	Wu, Gao-jun; Liang, Guang
作者单位	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
第一作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院; 药学院（分析测试中心）; 生物有机与药物化学研究中心
通讯作者单位	附属第一医院; 第一临床医学院（信息与工程学院）、附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Qian, Jin-fu,Liang, Shi-qi,Wang, Qin-yan,et al. Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure[J]. ACTA PHARMACOLOGICA SINICA,2023,45(3):531-544.
APA	Qian, Jin-fu., Liang, Shi-qi., Wang, Qin-yan., Xu, Jia-chen., Luo, Wu., ... & Liang, Guang. (2023). Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure. ACTA PHARMACOLOGICA SINICA, 45(3), 531-544.
MLA	Qian, Jin-fu,et al."Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure".ACTA PHARMACOLOGICA SINICA 45.3(2023):531-544.