Use this URL to cite or link to this record in EThOS:
Title: Bile acid G-protein coupled receptors signalling in the fetal heart
Author: Ibrahim, Effendi
ISNI:       0000 0004 8499 657X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Access from Institution:
Bile acids are recognised as bioactive signalling molecules. While they are known to influence arrhythmia susceptibility in cholestasis, there is limited knowledge about the underlying mechanisms. To delineate mechanisms underlying foetal heart rhythm disturbances in cholestatic pregnancy, we used FRET microscopy to monitor cAMP release and contraction measurements in isolated rodent neonatal cardiomyocytes. The unconjugated bile acids CDCA, DCA and UDCA and, to a lesser extent, CA were found to be relatively potent agonists for the GPBAR1 (TGR5) receptor and elicit cAMP release, whereas all glyco- and tauro- conjugated bile acids are weak agonists. The bile acid-induced cAMP production does not lead to an increase in contraction rate and seems to be mediated by the RI isoform of adenylate cyclase, unlike adrenaline-dependent release which is mediated by the RII isoform. In contrast, bile acids elicited slowing of neonatal cardiomyocyte contraction, indicating that other signalling pathways are involved. The conjugated bile acids were found to be partial agonists of the muscarinic M2, but not sphingosine-1-phosphate-2, receptors, and act partially through the Gi pathway. INT777, a potent TGR5 semisynthetic agonist, also elicits high cAMP release, however, does not affect cardiomyocytes contraction in either neonatal or adult cells. Both pre-treatment and co-treatment with INT777 don't prevent the slowing of contraction induced by bile acid TCA. This finding confirms the non-involvement of TGR5 activation in the modulation of cardiomyocyte contraction. Thus, cAMP-mediated signalling via TGR5 must be implicated in some not yet identified physiological processes in cardiomyocytes. For instance, the present work provides preliminary evidence that TGR5 signalling may have an anti-fibrotic action. In hypoxia, when fibroblasts become activated and transform into myofibroblasts, treatment with INT777 inhibits this transformation. Further, in genetically deficient TGR5-/- mice, this inhibition is abolished. The suitability of TGR5 signalling as a potential therapeutic target in cardiac fibrosis needs to be explored in future experiments.
Supervisor: Gorelik, Julia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral