Anne-Marie Koop

266 either up- or downregulated, between the two groups ( figure 4a, supplemental table 2 ). Generation of a heatmap representing the 100 most differentially expressed transcripts between the experimental groups disclosed 17 downregulated and 83 upregulated genes in the banded WT animals ( figure 4b ). Among the top upregulated, we found several collagens and fibrotic related genes (Collagen type VIII, type IV and type XVI alpha 1 chain, Col8a1 , Col4a1 and Col16a1 ; Periostin, Postn ; and Transforming growth factor beta-3, Tgf β 3 ) but also hypertrophic (Natriuretic peptide A and B, Nppa and Nppb , respectively; Myocilin, Myoc ) and inflammatory genes (Interleukin 17 receptor C, Il17rc and Chemokine C-motif ligand 21A serine, Ccl21a ) ( figure 4b ). After compiling our list of PAB-associated genes, we undertook a gene ontology enrichment analysis of this gene set, processing genes in terms of their associated molecular function. The top 20 GO terms based on biological processes and ranked by fold-enrichment are shown in figure 4c . This top-rank included biological processes such as “extracellular matrix-receptor interaction, collagen trimer, neutrophil chemotaxis, cell adhesion and chemokine signaling, receptor binding and activity. The KEGG pathway analysis results revealed that the differentially expressed genes were highly associated with several pathways, including “TNF-signaling pathway”, “hypertrophic cardiomyopathy”, “dilated cardiomyopathy”, “ECM-receptor interaction” as well as “chemokine signaling” ( figure 4d ). These results indicate that cardiac remodelling induced by PAB involves genes that are directly related to fibrosis, ECM remodelling, vascular function and inflammation, in agreement with the RV and LV phenotypes observed in mice that were subjected to PAB.