Acute myocardial infarction leads to distinct sex differences in the coding transcriptome of human monocytes with a potential impact in disease aetiopathology
Authors: Kratzer A , Giral H , Franke V , Moobed M , Meteva D , Jakob P , Akalin A , Landmesser U 
Published: October 2024

Abstract

Background
Immune responses are intricately linked to human disease, not only during pathogenic infections but also in sterile injury events such as in cardiovascular disease. Atherosclerosis is the main driver leading to coronary artery disease (CAD) and subsequent development of acute myocardial infarction (AMI) and heart failure. The vital role of monocytes in the pathophysiology of atherosclerosis is well established. In the onset of AMI, monocytes act as first responders, both in the inflammatory and tissue repair phases. It is now apparent that sex-specific differences in the inflammatory responses leading to AMI impact the severity and outcome of patients. Yet, the immune responses during AMI have been under-investigated in women, often under-represented in clinical studies, and more research in this topic is required.

Purpose
Identification of sex-specific differences in the coding transcriptome of monocytes subpopulations in the onset of AMI compared to matched healthy subjects and CAD patients.

Methods
We isolated monocytes from male and female AMI patients, CAD patients and healthy controls. FACS sorting of monocytes (CD14 and CD16) resulted into classical, intermediate, and non-classical subpopulations. We performed ribosomal depletion and bulk Illumina RNA sequencing for each monocyte subpopulation. Differentially expressed genes (DEG) were calculated using specific R packages. Pathway enrichment analysis was performed with Gene set enrichment analysis (GSEA). Other computational tools were used to determine enrichment of genes linked to GWAS identified in cardiovascular diseases or to infer pathway responsive genes upon perturbation (Progeny). Network comparison and visualization were performed using Cytoscape platform.

Results
Whereas observing a clear overlap of most pathways such as homeostasis, regulation of signalling cascades and inflammatory response, we also identified other pathways contrasting strongly between both sexes. In fact, TGF beta/ SMAD signalling, wound healing and epithelial to mesenchymal transition are increased in female cells. On the contrast the more pro-inflammatory BMP/SMAD signalling is increased in male cells accompanied by decreased respiratory electron transport and translation. Additionally, when comparing our data to signatures identified in trauma patients, we observe clear mapping of our gene sets, which are upregulated in AMI, with the first 3 trauma associated signatures, whereas one of the signatures associated to homeostasis associates clearly with our CAD data as well as the healthy subjects.

Conclusions
Human monocytes display a specific coding transcriptome and certain pathways are differentially expressed in AMI and differ greatly between male and female cohorts. Interestingly, our DEG map closely to trauma associated signatures, highlighting potential similarities in disease aetiopathology between trauma and AMI patients.