This study explores the role of oxidative stress and the CEBPB/HMGB1/VCAM1 signaling axis in sepsis-exacerbated coronary artery disease (CAD).
Methods:
A sepsis-exacerbated CAD model was established in male ApoE−/− mice using cecal ligation and puncture (CLP) surgery followed by a high-fat diet (HFD) to induce coronary atherosclerosis. Lentiviral-mediated overexpression and knockdown of CEBPB and VCAM1 were performed via tail vein injection. In vitro experiments employed THP-1-derived macrophages and human aortic endothelial cells (HAECs). Key methodologies included single-cell RNA sequencing, bulk transcriptomics, chromatin immunoprecipitation, dual-luciferase reporter assays, enzyme-linked immunosorbent assay, reactive oxygen species (ROS) detection, and flow cytometry to elucidate the molecular mechanisms of the CEBPB/HMGB1/VCAM1 axis.
Results:
CEBPB was upregulated in macrophages under septic conditions, promoting HMGB1 transcription and triggering pyroptosis and ROS overproduction. Released HMGB1 enhanced macrophage–endothelial adhesion and upregulated VCAM1 expression in endothelial cells (ECs) via the NF-κB pathway, contributing to endothelial dysfunction. These effects were validated in vivo using the CLP + HFD mouse model, where CEBPB knockdown or VCAM1 overexpression modulated inflammatory and vascular markers. In vitro, functional damage to ECs was observed upon co-culture with activated macrophages, but this was alleviated by targeting HMGB1 or VCAM1.
Innovation:
The CEBPB/HMGB1/VCAM1 axis links systemic inflammation to oxidative vascular damage in sepsis, offering a therapeutic target for CAD complications.
Conclusion:
The findings provide novel insights into the interplay of oxidative stress and inflammatory signaling in sepsis-exacerbated CAD, suggesting actionable strategies to prevent cardiovascular complications. Antioxid. Redox Signal. 43, 886–912.
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