KLX mitigates atherosclerotic progression by preventing EndMT

Atherosclerosis, a disease characterized by the accumulation of lipids and inflammatory cells in the arterial wall, is a significant cause of cardiovascular events. A key process in atherosclerosis is the endothelial-to-mesenchymal transition (EndMT), which involves the transformation of endothelial cells into mesenchymal cells, contributing to plaque formation and vascular dysfunction. The novel anthraquinone compound Kanglexin (KLX) has been investigated for its potential to prevent EndMT in atherosclerosis by targeting the fibroblast growth factor receptor 1 (FGFR1) and suppressing the integrin β1/transforming growth factor-beta (TGFβ) signaling pathway. This study provides insights into the molecular mechanisms underlying the protective effects of KLX against EndMT and atherosclerotic progression.

The research focused on the effects of KLX on human umbilical vein endothelial cells (HUVECs) subjected to TGFβ1-induced EndMT and on atherosclerotic lesions in ApoE-/- mice fed a high-fat diet. KLX was found to mitigate morphological changes, reduce collagen synthesis, and restore intercellular connectivity in TGFβ1-induced HUVECs. It also attenuated the downregulation of endothelial markers and the upregulation of mesenchymal markers, indicating its potential to inhibit EndMT. In vivo, KLX treatment reduced lipid deposition, plaque formation, and collagen secretion in the aortic roots of mice, suggesting its efficacy in alleviating aortic EndMT and atherosclerosis.

The study further explored the molecular mechanisms of KLX's action, revealing that KLX activates FGFR1, which in turn activates MAP4K4, leading to the inactivation of integrin β1 and the suppression of TGFβR/Smad signaling. This cascade of events results in the inhibition of EndMT. The activation of FGFR1 by KLX was confirmed through the observation of increased interactions between phosphorylated FGFR1 and MAP4K4, and the inhibition of this pathway by a FGFR1 inhibitor reversed KLX's effects. These findings highlight the role of KLX in modulating key signaling pathways involved in EndMT and atherosclerosis, offering a potential therapeutic strategy for these conditions.

In conclusion, KLX exhibits protective effects against EndMT and atherosclerosis by activating the FGFR1/MAP4K4 pathway and suppressing the integrin β1/TGFβ signaling pathway. This study's findings position KLX as a promising candidate for the prevention and treatment of vascular EndMT and atherosclerosis, with potential clinical applications in managing cardiovascular diseases.