Day 1 Post‐Myocardial Infarction Cardiac Macrophage Transcriptomic Signatures that Link to LV Infarct Wall Thinning

Abstract

We evaluated the relationships between the macrophage transcriptome at day 1 following myocardial infarction (MI) and infarct wall thinning. C57BL/6J male mice (3–6 months old) were subjected to permanent coronary artery ligation to induce MI, and macrophages were isolated from the infarct region at day 1 post‐MI. Day 0 no MI cardiac macrophages served as the negative control. Whole transcriptome analysis was performed using next‐generation RNA sequencing (Illumina NextSeq 500 platform) on n=4 pooled sets for each time, representing a total of 59 mice. Infarct wall thinning (Day 0 – Day 1) was assessed by echocardiography. A total of 16,696 genes were quantified and passed quality control (FPKM > 0 for at least 3 replicates per group). Of these, 3,062 were differentially expressed (fold change ≥ 2.0, p<0.05), of which 1,019 were upregulated and 2,043 were downregulated. Gene ontology pathways enriched for the upregulated genes included inflammatory response and response to hypoxia, while pathways enriched for the downregulated genes included extracellular matrix organization. To determine potential contributions of individual genes to the wall thinning phenotype, large scale correlation analysis was performed. Of the 3,062 differentially expressed genes, 119 positively correlated with the decrease in wall thickness, while 93 negatively correlated. Of interest, positive correlations between several pro‐inflammatory genes and wall thinning were observed, includingTlr1 (r=0.99, p=0.01), Tnfrsf1b (r=0.95; p=0.047), Hrh4 (r=0.96; p=0.036), and Stat5a (r=0.95; p=0.048), all of which play pro‐inflammatory roles in response to inflammatory stimuli. Genes that negatively correlated with wall thinning included Vegfa (r=−0.96, p=0.04) and Nfkbie (r=−0.99, p=0.009), which are negative regulators of inflammation. Of the positively correlated genes, NF‐kappaB was a major enriched pathway (p=0.009), suggesting excessive NF‐kappaB signaling in macrophages exacerbates post‐MI wall thinning. For negatively correlated genes, Kit signaling, which has been linked to immune suppression and the anti‐inflammatory M2 phenotype, was a major enriched pathway (p=0.00001). Combined, these results indicate that promoting pro‐inflammatory and limiting anti‐inflammatory gene expression in post‐MI day 1 cardiac macrophages is directly linked to LV wall thinning.Support or Funding InformationFunding: NIH GM103328, GM103476, GM104357, GM114833, GM115428, HL051971, HL075360, HL105324, HL129823, AHA 15SDG22930009, and VA 5I01BX000505 and IK2BX003922This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.