Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

doi:10.1016/j.apsb.2024.01.013

科研成果详情

题名	Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes
作者	Chen, Xiong1,2,3; Qian, Jinfu4; Liang, Shiqi2,4; Qian, Jianchang2; Luo, Wu2; Shi, Yujuan 1,2; Zhu, Hong1; Hu, Xiang1; Wu, Gaojun4; Li, Xiaokun2,3; Liang, Guang1,2,5
发表日期	2024-04
发表期刊	Acta Pharmaceutica Sinica B; 影响因子和分区
语种	英语
原始文献类型	Article
关键词	c-Src Cardiomyocytes Diabetic cardiomyopathy FGFR1 Inflammatory responses NFκB Protein tyrosine kinases Toll-like receptor 4
其他关键词	GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE ; CARDIAC DAMAGE ; HEART-FAILURE ; MECHANISMS ; TLR4 ; EGFR ; INHIBITION ; EXPRESSION ; PROTECTS
摘要	Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
资助项目	National Key Research Project[2017YFA0506000];National Natural Science Foundation of China[81930108,82000793,82270364];
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
ISSN	2211-3835
EISSN	2211-3843
卷号	14 期号:4 页码:1693-1710
DOI	10.1016/j.apsb.2024.01.013
页数	18
WOS类目	Pharmacology & Pharmacy
WOS研究方向	Pharmacology & Pharmacy
WOS记录号	WOS:001216657600001
收录类别	SCOPUS ; PUBMED ; SCIE ; 万方 ; ISTIC ; CSCD
URL	查看原文
PubMed ID	38572108
SCOPUSEID	2-s2.0-85186072435
通讯作者地址	[Liang, Guang]Department of Endocrinology,the First Affiliated Hospital,Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Pharmacology, Toxicology and Pharmaceutics (all)
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/210635
专题	附属第一医院药学院（分析测试中心）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	Liang, Guang
作者单位	1.Department of Endocrinology,the First Affiliated Hospital,Wenzhou Medical University,Wenzhou,325035,China; 2.Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,325035,China; 3.Department of Wound Repair,the First Affiliated Hospital,Wenzhou Medical University,Wenzhou,325035,China; 4.Department of Cardiology,the First Affiliated Hospital,Wenzhou Medical University,Wenzhou,325035,China; 5.School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou,311399,China
第一作者单位	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
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Chen, Xiong,Qian, Jinfu,Liang, Shiqi,et al. Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes[J]. Acta Pharmaceutica Sinica B;,2024,14(4):1693-1710.
APA	Chen, Xiong., Qian, Jinfu., Liang, Shiqi., Qian, Jianchang., Luo, Wu., ... & Liang, Guang. (2024). Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes. Acta Pharmaceutica Sinica B;, 14(4), 1693-1710.
MLA	Chen, Xiong,et al."Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes".Acta Pharmaceutica Sinica B; 14.4(2024):1693-1710.