Ox-LDL induces a non-inflammatory response enriched for coronary artery disease risk in human endothelial cells

Journal article

Oxidised low-density lipoprotein cholesterol (ox-LDL) is critical in the initiation and progression of atherosclerosis. While excessive atherogenic lipids in the arterial intima can trigger endothelial dysfunction in advanced lesions, the response of endothelial cells to ox-LDL in the early stages of atherogenesis remains unclear. Here, we conducted a comprehensive, genome-wide multi-omics characterisation of the cellular response to ox-LDL in primary human aortic endothelial cells (HAECs). Our results reveal that the exposure of HAECs to ox-LDL leads to pathogenic changes in metabolism, transcriptome and epigenome, but in the absence of a typical inflammatory endothelial phenotype. An integrative analysis implicates the role of AP-1, NFE-2 and CEBP transcription factors in regulating ox-LDL-induced transcription. We further demonstrate that ox-LDL activates endothelial cell migration through the epigenomic rewiring of transcription factor binding. Notably, these ox-LDL-induced dynamic binding sites are enriched for the genetic risk of coronary artery disease, enabling the discovery of the gene-environment interaction of rs62172376 and ox-LDL at the CALCRL/TFPI locus. Collectively, our findings provide an unbiased understanding of the transcriptional regulation in endothelial cells in response to ox-LDL, together with its interaction with the genetic element of coronary artery disease.

Authors: Jiang, J; Hiron, TK; Chalisey, A; Malhotra, Y; Agbaedeng, T

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 15
• Issue: 1
• Pages: 21877-21877
• Article number: 21877
• Publication date: 2025-07-01
• Acceptance date: 2025-06-17
• DOI: 10.1038/s41598-025-07763-3
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Transcription factor; Transcriptome; Epigenomics; Biology; Coronary artery disease; Epigenome; Endothelial dysfunction; Endothelium; Lipoprotein; Cholesterol; Phenotype; Inflammation; Immunology; Cell biology; Cancer research; Gene; Medicine; Internal medicine; Genetics; Endocrinology; Gene expression; DNA methylation