MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappa B signaling pathway

doi:10.1007/s00395-016-0599-5

科研成果详情

题名	MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappa B signaling pathway
作者	Han, Jibo1,2; Zou, Chunpeng3; Mei, Liqin4; Zhang, Yali1; Qian, Yuanyuan1; You, Shengban2; Pan, Yong 1; Xu, Zheng 1; Bai, Bin1; Huang, Weijian2; Liang, Guang1
发表日期	2017-01
发表期刊	BASIC RESEARCH IN CARDIOLOGY 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Myeloid differentiation 2 Angiotensin II Toll-like receptor 4 Inflammation Cardiac remodeling
其他关键词	NECROSIS-FACTOR-ALPHA ; HEART-FAILURE ; RECEPTOR 4 ; INDUCED HYPERTENSION ; KAPPA-B ; HYPERTROPHY ; MD-2 ; FIBROSIS ; DYSFUNCTION ; INHIBITION
摘要	Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and profibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subc2utaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81622043, 81470565, 81503123, 81670244, 81302821]; Natural Science Funding of Zhejiang Province [LR16H310001]
出版者	SPRINGER HEIDELBERG
出版地	HEIDELBERG
ISSN	0300-8428
EISSN	1435-1803
卷号	112 期号:1 页码:9
DOI	10.1007/s00395-016-0599-5
页数	15
WOS类目	Cardiac & Cardiovascular Systems
WOS研究方向	Cardiovascular System & Cardiology
WOS记录号	WOS:000392310300009
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	28013347
SCOPUSEID	2-s2.0-85006980221
自科自定义期刊分类	T3(A)类
通讯作者地址	[Liang, Guang]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Physiology;Cardiology and Cardiovascular Medicine;Physiology (medical)
引用统计	被引频次：67[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/12495
专题	药学院（分析测试中心）附属第二医院附属第一医院第二临床医学院、附属第二医院、育英儿童医院口腔医学院、附属口腔医院第二临床医学院、附属第二医院、育英儿童医院_影像医学与核医学_超声科
通讯作者	Liang, Guang
作者单位	1.Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China; 2.Department of Cardiology,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou,China; 3.Department of Ultrasonography,The Second Affiliated Hospital,Wenzhou Medical University,Wenzhou,China; 4.Department of Oral Prophylaxis and Hygiene,School and Hospital of Stomatology,Wenzhou Medical University,Wenzhou,China
第一作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心; 附属第一医院
通讯作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Han, Jibo,Zou, Chunpeng,Mei, Liqin,et al. MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappa B signaling pathway[J]. BASIC RESEARCH IN CARDIOLOGY,2017,112(1):9.
APA	Han, Jibo., Zou, Chunpeng., Mei, Liqin., Zhang, Yali., Qian, Yuanyuan., ... & Liang, Guang. (2017). MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappa B signaling pathway. BASIC RESEARCH IN CARDIOLOGY, 112(1), 9.
MLA	Han, Jibo,et al."MD2 mediates angiotensin II-induced cardiac inflammation and remodeling via directly binding to Ang II and activating TLR4/NF-kappa B signaling pathway".BASIC RESEARCH IN CARDIOLOGY 112.1(2017):9.