Astragalus polysaccharide relieves chronic intermittent hypoxia-induced vascular endothelial dysfunction by inhibiting ferroptosis through activation of the Nrf2/SLC7A11/GPX4 axis.

Abstract

BACKGROUND: Vascular endothelial dysfunction (VED) is pivotal in diverse disorders, and ferroptosis (iron-dependent regulated cell death) is linked to cardiovascular diseases. Astragalus polysaccharide (APS), is a heterogeneous mixture of macromolecular polysaccharides and exerts multiple beneficial effects, but its role in VED remains unclear. PURPOSE: To explore the mechanism by which APS alleviates VED. METHODS: Rats and human pulmonary artery endothelial cells (HPAECs) were exposed to chronic intermittent hypoxia (CIH). In vivo, rats were treated with APS, ferrostatin-1 (a ferroptosis inhibitor), or APS combined with erastin (a ferroptosis activator) for 28 days. In vitro, additional treatments with nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA and ML385 (an Nrf2 inhibitor) were performed to comprehensively explore the protective mechanism of APS. VED was assessed via endothelium-dependent vasodilation (EDV), nitric oxide (NO) levels, and endothelial nitric oxide synthase (eNOS) expression. Ferroptosis was evaluated using transmission electron microscopy (TEM), Prussian blue staining, and Western blotting. Signaling pathway analysis was performed using Western blot, immunofluorescence, and molecular docking. RESULTS: CIH reduced endogenous antioxidants and induced lipid peroxidation and ferroptosis. APS promoted activation of the Nrf2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway, enhancing antioxidant capacity, suppressing lipid peroxidation, and reversing CIH-induced ferroptosis. Both ML385 and Nrf2 siRNA markedly suppressed the protective effects of APS by blockade of Nrf2. CONCLUSION: Ferroptosis contributes to CIH-induced VED. APS protects against ferroptosis through the Nrf2/SLC7A11/GPX4 axis, highlighting its therapeutic potential for ferroptosis-associated VED.

Key Findings

• Chronic intermittent hypoxia (CIH) induces vascular endothelial dysfunction (VED) by promoting ferroptosis.
• Astragalus polysaccharide (APS) activates the Nrf2/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity and suppressing lipid peroxidation to reverse CIH-induced ferroptosis.
• Inhibition of Nrf2 using ML385 or siRNA blocks the protective effects of APS, confirming the critical role of Nrf2 in mediating APS's benefits.

Clinical Significance

Citation

Wu Susu, Zhang Xiangfeng, Wei Silinet al.. Astragalus polysaccharide relieves chronic intermittent hypoxia-induced vascular endothelial dysfunction by inhibiting ferroptosis through activation of the Nrf2/SLC7A11/GPX4 axis. European journal of pharmacology. 2026-Aug-14.