Sex-specific differences in cytokine signaling pathways in circulating monocytes of cardiovascular disease patients

Chang Lu, Marjo M P C Donners*, Joël Karel, Hetty de Boer, Anton Jan van Zonneveld, Hester den Ruijter, J Wouter Jukema, Adriaan Kraaijeveld, Johan Kuiper, Gerard Pasterkamp, Rachel Cavill, Javier Perales-Patón, Ele Ferrannini, Pieter Goossens, Erik A L Biessen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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BACKGROUND AND AIMS: This study aims to identify sex-specific transcriptional differences and signaling pathways in circulating monocytes contributing to cardiovascular disease.

METHODS AND RESULTS: We generated sex-biased gene expression signatures by comparing male versus female monocytes of coronary artery disease (CAD) patients (n = 450) from the Center for Translational Molecular Medicine-Circulating Cells Cohort. Gene set enrichment analysis demonstrated that monocytes from female CAD patients carry stronger chemotaxis and migratory signature than those from males. We then inferred cytokine signaling activities based on CytoSig database of 51 cytokine and growth factor regulation profiles. Monocytes from females feature a higher activation level of EGF, IFN1, VEGF, GM-CSF, and CD40L pathways, whereas IL-4, INS, and HMGB1 signaling was seen to be more activated in males. These sex differences were not observed in healthy subjects, as shown for an independent monocyte cohort of healthy subjects (GSE56034, n = 485). More pronounced GM-CSF signaling in monocytes of female CAD patients was confirmed by the significant enrichment of GM-CSF-activated monocyte signature in females. As we show these effects were not due to increased plasma levels of the corresponding ligands, sex-intrinsic differences in monocyte signaling regulation are suggested. Consistently, regulatory network analysis revealed jun-B as a shared transcription factor activated in all female-specific pathways except IFN1 but suppressed in male-activated IL-4.

CONCLUSIONS: We observed overt CAD-specific sex differences in monocyte transcriptional profiles and cytokine- or growth factor-induced responses, which provide insights into underlying mechanisms of sex differences in CVD.

Original languageEnglish
Article number117123
Number of pages10
Early online date14 Apr 2023
Publication statusPublished - Nov 2023


  • Coronary artery disease
  • Monocyte
  • Sex differences
  • Signaling activities
  • Transcription factor activities


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