Protective effect of UDCA against IL-11- induced cardiac fibrosis is mediated by TGR5 signalling
We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.
Authors
- Anastasia Shchendrygina (ORCID: https://orcid.org/0000-0002-8220-0350)
- Alice L. Mitchell (ORCID: https://orcid.org/0000-0002-6861-5779)
- Rasheda A. Chowdhury (ORCID: https://orcid.org/0000-0003-4204-1014)
- Cesare M. Terracciano (ORCID: https://orcid.org/0000-0003-2761-0696)
- Benedict Reilly-O’Donnell (ORCID: https://orcid.org/0000-0003-0183-3701)
- Catherine Williamson (ORCID: https://orcid.org/0000-0002-6226-7611)
- L. Patel
- Julia Gorelik (ORCID: https://orcid.org/0000-0003-1148-9158)
- Luciano Adorini (ORCID: https://orcid.org/0000-0001-8109-339X)
- Raquel Núñez-Toldrà (ORCID: https://orcid.org/0000-0002-8716-2138)
- Akifumi Endo (ORCID: https://orcid.org/0000-0002-8788-4042)
- Prashant K. Srivastava (ORCID: https://orcid.org/0000-0003-1454-5493)
- Fu Siong Ng (ORCID: https://orcid.org/0000-0002-8681-4368)
- Elisa Ferraro (ORCID: https://orcid.org/0000-0003-3284-5078)
- Roman Tikhomirov (ORCID: https://orcid.org/0009-0001-7831-8073)
- Yue Wu (ORCID: https://orcid.org/0000-0003-2893-0659)
Institutions
- King's College London (GB)
- Imperial College London (GB)
- Intercept Pharmaceuticals (United States) (US)
Publication Details
- Journal
- Frontiers in Cardiovascular Medicine
- Published
- 2024-12-03
- DOI
- https://doi.org/10.3389/fcvm.2024.1430772
- Citations
- 10
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 4.02
Funders
- British Heart Foundation
- Heart Research UK