Abstract 11257: The Monocyte Genomic Response is Conserved Between Mice and Humans Following Acute Myocardial Infarction
Background: Monocytes have critical functions in the innate immune response to acute myocardial infarction (AMI). In a mouse model, targeting monocytes reduces infarct size and adverse left ventricular remodelling. However, the relevance of these observations to human disease is unclear. We used gene-expression profiling of isolated peripheral blood monocytes in both mice and humans to test the hypothesis that the monocyte response following AMI was conserved between species.
METHODS: Female C57BL/6J mice underwent AMI by surgical coronary artery ligation or sham procedure. At 48 hours, CD11b+CD115+Ly6G- monocytes were isolated from blood following terminal anaesthesia by fluorescent activated cell sorting (n=6/group). Peripheral monocytes were isolated by negative selection from 30 patients acutely at the time of presenting with ST elevation myocardial infarction and after 48 hours, and from 24 patients with confirmed stable coronary atherosclerosis as controls. RNA from isolated monocytes was hybridised to Illumina beadchips.
RESULTS: Gene-expression analysis revealed 233 genes were significantly differentially expressed in mouse monocytes following AMI (P<0.01, FDR<0.25, fold change >1.5) and 122 genes in human monocytes following AMI (P<0.01, FDR<0.25, fold change >1.5). 14 genes including IL1R2 and LCN2 were significantly differentially expressed (P<0.01, FDR<0.25, fold change >1.5) in both species. A number of biological processes were significantly enriched in both datasets e.g. TLR signalling (P<0.01), integrin pathway (P<0.01) and inflammasome activation (P<0.01). Ingenuity pathway analysis identified a number of upstream regulators were conserved between both species e.g. IL6, IL1β, TNF-α (P<0.01) in addition to downstream functions including cell phagocytosis, cell mobility and cell-to-cell signalling (all P<0.001). Gene set enrichment analysis confirmed significant enrichment between datasets (P<0.01, FDR<0.25).
Conclusions: We conclude that the monocyte response following AMI is conserved between species, validating the experimental model for (1) investigation of pathogenesis of AMI (2) evaluating new immune-modulating therapeutics and (3) identifying potential therapeutic targets.
- © 2013 by American Heart Association, Inc.