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

作　　者：Xiong Chen Jinfu Qian Shiqi Liang Jianchang Qian Wu Luo Yujuan Shi Hong Zhu Xiang Hu Gaojun Wu Xiaokun Li Guang Liang 

机构地区：[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

出　　处：《Acta Pharmaceutica Sinica B》2024年第4期1693-1710,共18页药学学报（英文版）

基　　金：This study was supported by the National Key Research Project(2017YFA0506000 to Guang Liang,China);National Natural Science Foundation of China(81930108 to Guang Liang and 82000793 to Wu Luo,and 82270364 to Xiong Chen).

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.

关 键 词：Diabetic cardiomyopathy Protein tyrosine kinases FGFR1 CARDIOMYOCYTES Inflammatory responses Toll-like receptor4 C-SRC NFKB 

分 类 号：R96[医药卫生—药理学]