The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrin β1/TGFβ signaling.
10.1007/s11684-024-1077-3
- Author:
Yixiu ZHAO
1
;
Zhiqi WANG
1
;
Jing REN
1
;
Huan CHEN
1
;
Jia ZHU
1
;
Yue ZHANG
1
;
Jiangfei ZHENG
1
;
Shifeng CAO
1
;
Yanxi LI
2
;
Xue LIU
1
;
Na AN
3
;
Tao BAN
1
;
Baofeng YANG
4
;
Yan ZHANG
5
Author Information
1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
2. College of Basic Medicine, Harbin Medical University, Harbin, 150081, China.
3. Heilongjiang Medical Academy, Harbin Medical University, Harbin, 150081, China.
4. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. yangbf@ems.hrbmu.edu.cn.
5. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China. zhangyan@ems.hrbmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
EndMT;
FGFR1;
Kanglexin;
MAP4K4;
atherosclerosis;
integrin β1
- MeSH:
Animals;
Atherosclerosis/prevention & control*;
Mice;
Receptor, Fibroblast Growth Factor, Type 1/metabolism*;
Signal Transduction/drug effects*;
Anthraquinones/pharmacology*;
Humans;
Integrin beta1/metabolism*;
Epithelial-Mesenchymal Transition/drug effects*;
Male;
Transforming Growth Factor beta/metabolism*;
Disease Models, Animal;
Mice, Inbred C57BL;
Human Umbilical Vein Endothelial Cells/drug effects*
- From:
Frontiers of Medicine
2024;18(6):1068-1086
- CountryChina
- Language:English
-
Abstract:
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.
