Salidroside ameliorates macrophages lipid accumulation and atherosclerotic plaque by inhibiting Hif-1α-induced pyroptosis.

Abstract

Background: Hipoxia-inducible factor 1 alpha (Hif-1α) is a significant risk factor for atherosclerotic cardiovascular disease. Salidroside (SAL) has demonstrated anti-oxidative and anti-cardiovascular disease effects. Currently, there are no relevant studies investigating the interaction between SAL and Hif-1α in the progression of atherosclerosis.

Methods: Hif-1α was either knocked down or upregulated in Ana-1 macrophages-derived foam cells, and atherosclerosis ApoE^-/- mice were treated with or without SAL. A Protein-protein network involving Hif-1α and pyroptosis-related genes was identified through bioinformatic analysis and validated in human vascular tissues. The Oil Red O and DiI staining were used to detect the intracellular ox-LDL accumulation. The HE and Oil Red O staining were employed to evaluate atherosclerotic plaque in vivo. The levels of relevant molecules were quantified using WB, qRT-PCR, ELISA, and immunohistochemistry. The target proteins of SAL were identified through Molecular docking and Cell Thermal Shift Assay (CESTA).

Results: Both Hif-1α knockdown and SAL treatment markedly reduced lipid accumulation in macrophages-derived foam cells. Hif-1α was closely associated with Caspase1, Gsdmd, NRLP3, and IL-1β, and co-located in CD86⁺ macrophages-derived foam cells within atherosclerotic plaque. SAL inhibited Hif-1α-induced Caspase-1-dependent pyroptosis and lipid accumulation by directly bonding to Hif-1α. In vivo, SAL treatment decreased atherosclerotic plaque and improved plasma lipid profiles. Furthermore, SAL reduced M₁ macrophages infiltration and the levels of Hif-1α, C-Caspase1, Gsdmd-N, NRLP3, IL-18, and IL-1β in atherosclerotic plaque.

Conclusion: SAL alleviated the lipid accumulation in macrophages and atherosclerotic plaques by inhibiting pyroptosis pathway via directly binding to Hif-1α, which may be a promising therapeutic strategy for AS treatment.