The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrin β1/TGFβ signaling

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.

Keywords

atherosclerosis / EndMT / integrin β1 / FGFR1 / MAP4K4 / Kanglexin

Yixiu Zhao et al

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Acknowledgements

This work was financially supported by the Basic Research Support Program for Outstanding Young Teachers of Heilongjiang Province (No. YQJH2023038), the National Natural Science foundation of China (Nos. 82170431, 82070312, 82373868, 82330011, and U21A20339) and the Scientific Research Project of Provincial Scientific Research Institute of Heilongjiang Province (No. CZKYF2022-1-B007).

Compliance with ethics guidelines

Conflicts of interest Yixiu Zhao, Zhiqi Wang, Jing Ren, Huan Chen, Jia Zhu, Yue Zhang, Jiangfei Zheng, Shifeng Cao, Yanxi Li, Xue Liu, Na An, Tao Ban, Baofeng Yang, and Yan Zhang declare that they have no conflict of interest. Baofeng Yang is a member of the Editorial Board of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

All institutional and national guidelines for the care and use of laboratory animals were followed.

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