Cellular signalling · 2026
Preclinical investigation on the anti-atherosclerotic effects of Tenuifolin via modulation of endothelial-mesenchymal transition in animal models.
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Yang Xuemei, Wang Fan, Bi Tao, Chen Lei, Wang Ting, Huang Juan, Dai Xiyu, Zhao Qixin, Yao Shengdan, Sun Qin, Liu Zengjin, Xu Houping
Аннотация
BACKGROUND: Atherosclerosis (AS) has emerged as a leading contributor to the global burden of cardiovascular disease. Consequently, identifying effective and safe therapeutic candidates targeting the pathophysiology of AS is of paramount importance for improving treatment outcomes. Tenuifolin (TEN), a triterpenoid compound isolated from Polygala tenuifolia, exhibits a wide array of pharmacological activities, including neuroprotection, immunomodulatio, and pulmonary protection. However, there is currently a paucity of evidence substantiating the therapeutic efficacy and underlying pharmacological mechanisms of TEN in the management of AS. Therefore, this study aims to systematically evaluate the therapeutic potential of TEN in AS and investigate its associated pharmacological mechanisms.
METHOD: ApoE-/- mice were fed a high-fat diet (HFD) to establish an in vivo AS model and were treated with TEN. The effects of TEN on atherosclerotic lesions, lipid metabolism, inflammation, and EndMT were evaluated using serological assays, histological staining, immunofluorescence, metabolomics, and targeted UHPLC-Orbitrap HRMS analysis. The underlying mechanism was further explored by molecular dynamics simulations and in vitro experiments using ox-LDL-stimulated HUVECs.
RESULT: TEN treatment markedly alleviated HFD-induced atherosclerotic lesions, reduced lipid deposition, improved serum lipid profiles, and attenuated vascular inflammation and fibrosis. Metabolomic analysis further supported the beneficial effects of TEN on AS-associated metabolic disturbances. Targeted UHPLC-Orbitrap HRMS confirmed that TEN was detectable in whole-aorta homogenates after administration, supporting aortic tissue exposure. In both HFD-induced mice and ox-LDL-treated HUVECs, TEN attenuated EndMT-associated changes, as evidenced by increased endothelial markers CD31 and VE-cadherin and decreased mesenchymal markers α-SMA, FSP1, and fibronectin. Mechanistically, TEN suppressed STAT1 phosphorylation, potentially through modulation of the JAK1/STAT1 signaling axis.
CONCLUSION: TEN exerts protective effects against experimental AS, at least partly by attenuating EndMT-associated vascular remodeling through suppression of JAK1/STAT1 signaling. These findings suggest that TEN may serve as a promising therapeutic candidate for AS.
METHOD: ApoE-/- mice were fed a high-fat diet (HFD) to establish an in vivo AS model and were treated with TEN. The effects of TEN on atherosclerotic lesions, lipid metabolism, inflammation, and EndMT were evaluated using serological assays, histological staining, immunofluorescence, metabolomics, and targeted UHPLC-Orbitrap HRMS analysis. The underlying mechanism was further explored by molecular dynamics simulations and in vitro experiments using ox-LDL-stimulated HUVECs.
RESULT: TEN treatment markedly alleviated HFD-induced atherosclerotic lesions, reduced lipid deposition, improved serum lipid profiles, and attenuated vascular inflammation and fibrosis. Metabolomic analysis further supported the beneficial effects of TEN on AS-associated metabolic disturbances. Targeted UHPLC-Orbitrap HRMS confirmed that TEN was detectable in whole-aorta homogenates after administration, supporting aortic tissue exposure. In both HFD-induced mice and ox-LDL-treated HUVECs, TEN attenuated EndMT-associated changes, as evidenced by increased endothelial markers CD31 and VE-cadherin and decreased mesenchymal markers α-SMA, FSP1, and fibronectin. Mechanistically, TEN suppressed STAT1 phosphorylation, potentially through modulation of the JAK1/STAT1 signaling axis.
CONCLUSION: TEN exerts protective effects against experimental AS, at least partly by attenuating EndMT-associated vascular remodeling through suppression of JAK1/STAT1 signaling. These findings suggest that TEN may serve as a promising therapeutic candidate for AS.