The RNA-binding protein HuR controls atherosclerotic disease progression of carotid and femoral arteries

Clin Res Cardiol (2026). DOI 10.1007/s00392-026-02870-1
M. Sachse (Mannheim)¹, G. Georgiopoulos (Athens)², K. Sopova (Mannheim)³, M. Polycarpou-Schwarz (Mannheim)⁴, G. Ciliberti (Mannheim)⁵, A. Turchinovich (Mannheim)⁴, G. Mavraganis (Athens)⁶, S. Tual-Chalot (Newcastle Upon Tyne)⁷, M. Sigl (Mannheim)⁸, K. Stamatelopoulos (Athens)², K. Stellos (Mannheim)^9
1Department of Cardiovascular Research, Heidelberg University Mannheim, Deutschland; ²National and Kapodistrian University of Athens Department of Clinical Therapeutics Athens, Deutschland; ³Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; ⁴Medizinische Fakultät Mannheim der Universität Heidelberg Abteilung für Herz- Kreislaufforschung Mannheim, Deutschland; ⁵Universitätsklinik Mannheim Abteilung für Herz- und Kreislaufforschung Mannheim, Deutschland; ⁶Alexandra General Hospital Department of Clinical Therapeutics Athens, Griechenland; ⁷Newcastle University Newcastle Upon Tyne, Großbritannien; ⁸University Medical Centre Mannheim Department of Medicine VI, Mannheim, Deutschland; ⁹ University Medical Centre Mannheim Department of Medicine VI Mannheim, Deutschland

Introduction  The RNA-binding protein HuR (ELAVL1) is a post-transcriptional regulator of gene expression potentially implicated in vascular inflammation, thrombosis, and endothelial dysfunction. Here, we explored the functional role of HuR in human atherosclerotic arterial disease, and its influence on endothelial cell–mediated inflammatory processes.
Methods Expression of HuR expression was measured single-cell RNA-sequencing and in peripheral blood mononuclear cells (PBMCs) from 977 individuals at risk for atherosclerotic vascular disease. Carotid and femoral artery ultrasound assessed subclinical disease via intima-media thickness, maximum wall thickness, and plaque count. Participants were followed longitudinally for major adverse cardiovascular events (MACE). Mechanistically, HuR silencing or overexpression, RNA stability assays and pharmacological inhibition determined the effect of endothelial HuR in endothelial pro-inflammatory responses. HuR -mRNA interactome was characterized by HuR protein-RNA interactome assays (iCLiP-seq, RIP-seq).
Results Single cell analysis revealed increased HuR expression levels in vascular endothelium and infiltrated immune cells derived from a) Ldlr^-/- mice treated with high-fat diet compared to chow diet, b) human carotid atherosclerotic plaques and c) diseased coronary arteries compared to controls. In humans, HuR mRNA expression was increased in CCS compared to non-coronary artery disease (CAD) participants (p<0.001). Increased HuR expression was independently associated with the presence of CAD (OR=2.67 for highest vs. lower HuR tertiles), higher C-reactive protein (mean increase 23.6%) and mean carotid IMT after adjustment for traditional risk factors (P<0.05 for all). In the non-CAD population, increased HuR at baseline was prospectively associated with accelerated progression of subclinical atherosclerosis reflected as increased number of carotid and femoral plaques at follow-up (P<0.001) and a higher rate of increase in maxWT compared to patients at lower tertiles (P for interaction=0.045). Furthermore, high HuR concentrations were independently associated with higher 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). Mechanistically, endothelial cell HuR iCLiP-seq and RIP-seq revealed several HuR binding sites in AUUUA- and UUUU(G/U)-enriched 3¢UTRs of several pro-inflammatory and pro-thrombotic genes. Pharamcological inhibition or siRNA-mediated silencing of HuR reduces TNF-alpha cytokine-induced endothelial pro-inflammatory responses, while overexpression of HuR alone induces an EC pro-inflammatory phenotype by regulating the RNA stability of HuR targetome. Finally, HuR target mRNA expression correlated with HuR mRNA expression in patients with atherosclerosis.
Conclusion HuR inhibition poses as a promising therapeutic target in atherosclerosis by controling the RNA stability of several pro-atherosclerotic genes.