UDCA and INT-777 suppress cardiac fibrosis triggered by IL-11 through involvement of TGR5

Abstract

Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts (FB) into myofibroblasts (MFB). Myofibroblasts produce large quantities of extracellular matrix proteins, resulting in myocardial scar. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis but not the adult myocardium.Our hypothesis is: UDCA is antifibrotic in the adult heart, mediated by the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5).We constructed a predictive network of fibrosis using RNA-seq datasets. We found that UDCA and it’s analogue INT-777, both reduced MFB markers in rat and human FBs and living myocardial slices (LMS). Utilising a knock-out mouse model, we show that the antifibrotic effect of UDCA is mediated by TGR5. Finally, we performed RNA-seq upon UDCA-treated human FB and integrated with our network of fibrosis, establishing the mechanism of TGR5 agonists.

Interleukin 11-induced microRNAs as functional mediators and circulating biomarkers of cardiac fibrosis

“…Recently, Dai et al demonstrated that mice with endothelial-specific EGLN1 gene deletion exhibited left ventricle hypertrophy and cardiac fibrosis and identified HIF2α as a transcriptional factor responsible for the pro-fibrotic signalling [43]. Interestingly, IL-11 differential co-expression network is enriched in genes associated with hypoxia (e.g., HIF2α, VEGFC, CITED2) [37]. These findings are in keeping with previous reports of EGLN2 to be a target of miRNA-497-5p [44], and with our demonstration that miRNA-27b-5p directly binds to and suppresses EGLN1 mRNA expression.…”

“…The Imperial BRC Genomics facility performed RNAseq. Further differential gene expression analysis was performed using the EdgeR [36] tool implemented in R as described previously [37].…”