SULF1's Role in Endothelial Senescence and Atherosclerosis: Insights from Single-Cell and Bulk Transcriptomics

Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms underlying endothelial senescence in atherosclerosis remain poorly understood.

Single-cell RNA sequencing (scRNA-seq) data from atherosclerotic core plaques and adjacent normal tissues were analyzed using the Seurat package to identify cell subpopulations and senescence markers. RNA-seq data from early and late atherosclerotic plaques were used for differential gene expression analysis. Subsequently, the candidate gene was identified and validated in the atherosclerotic plaques of ApoE^-/- mice and ox-LDL-treated human aortic ECs (HAECs) through siRNA knockdown, Western blot, RT-qPCR, and β-galactosidase staining in vitro.

Single-cell analysis revealed elevated levels of senescence markers in ECs within atherosclerotic plaques. Combined with bulk RNA-seq analysis, SULF1 was identified as a key gene associated with EC senescence. Increased Sulf1 expression was uncovered in the ECs of atherosclerotic plaques in high-fat-fed ApoE^-/- mice. In vitro, SULF1 expression was found significantly upregulated in senescent HAECs. Knockdown of SULF1 reversed ox-LDL-induced senescence in HAECs, as shown by reduced expression of senescence markers and improved cell migration in wound healing assays.

This study highlights the critical role of endothelial senescence in atherosclerosis and identifies SULF1 as a key contributor to endothelial senescence and atherogenesis. Targeting SULF1 may be a potential therapeutic strategy for mitigating EC senescence and atherosclerosis.