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O053 - RNA-BINDING PROTEIN HUR CONTROLS VASCULAR ENDOTHELIAL CELL INFLAMMATORY RESPONSES TO TUMOR NECROSIS FACTOR-A AND IS ASSOCIATED WITH ATHEROSCLEROSIS PROGRESSION IN HUMANS (ID 162)
Abstract
Background and Aims
RNA-binding protein HuR may control the fate of pro-inflammatory and pro-thrombotic genes in human atherosclerosis.
Methods
Single-cell RNA-sequencing (scRNA)-data were analyzed to compare cell-specific expression profiles of HuR and its target genes in murine and human atherosclerotic vascular disease. HuR individual-nucleotide cross-linking and immunoprecipitation (iCLiP), small interfering RNA-mediated HuR silencing, HuR overexpression and RNA stability assays were used to determine HuR-mediated regulation of pro-atherosclerotic genes. Expression levels of HuR were measured in peripheral blood mononuclear cells derived from 718 individuals at risk for cardiometabolic disease or with established chronic coronary syndromes (CCS) and followed for major adverse cardiovascular events (MACE).
Results
scRNA-data revealed increased HuR expression levels in vascular endothelium and infiltrated immune cells. HuR iCLiP experiments revealed HuR binding sites in the 3’ untranslated region of several genes in endothelial cells. Silencing of HuR reduces, overexpression of HuR induces the expression of targeted genes (P<0.05 for all). Inhibition of transcription by actinomycin D showed that endothelial HuR controls the mRNA stability of CCL2, CTSS, CXCL1, CXCL2 and SERPINE1 (P<0.05 for all). In humans, HuR mRNA expression was increased in CCS compared to non-coronary artery disease (CAD) participants (p<0.001) and independently associated with the presence of CAD (OR=2.67 for highest vs. lower HuR tertiles) after adjustment for traditional risk factors. High HuR concentrations independently associated with MACE incidence across a median follow-up period of 48 months (higher versus lowest tertile: 7.4% vs. 1.27%, log rank test P=0.009).
Conclusions
HuR controls the stability of pro-atherosclerotic targets, predicts the progression of atherosclerosis and MACE in humans.