Abstract
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 fetal 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 sphingosin-1-phosphate-2, receptors, and act partially through the Gi pathway. Furthermore, the contraction slowing effect of unconjugated bile acids may also relate to cytotoxicity at higher concentrations.
Highlights
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder that typically presents in the third trimester of pregnancy
Conjugated bile acids are not such potent agonists of TGR5 in Neonatal mouse ventricular cardiomyocytes (NMVMs). This is an important observation, but unlikely to be of clinical relevance in the context of ICP because the principal BA in the fetal circulation are TCA, GCA, TCDCA and GCDCA11, there are very few unconjugated BA in the fetal circulation
chenodeoxycholic acid (CDCA) is a selective agonist for the nuclear receptor farnesoid X receptor (FXR), the most potent among endogenous bile acids[36,37]
Summary
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder that typically presents in the third trimester of pregnancy. Characterised by maternal pruritus, abnormal liver function and increased maternal serum bile acids, ICP is complicated by increased rates of adverse pregnancy outcomes, including spontaneous preterm labour and stillbirth[3,4]. While serum bile acid concentrations of ≥40 μmol/L are associated with adverse pregnancy outcomes, it has been shown that as maternal serum concentrations of bile acids rise further, www.nature.com/scientificreports/. The concentration of bile acids in the fetal serum is typically lower than in maternal serum, but they are both raised in ICP, and in untreated pregnancies the principal fetal bile acids are tauro- and glyco-conjugates of CA and CDCA14. It was proposed that ICP-associated fetal arrhythmia and intrauterine death may result from raised tauro-conjugated bile acids[6], and previous work has focussed on the arrhythmogenic effects of TCA on cardiomyocytes and myofibroblasts[15,16]. TCA is not the only bile acid to be elevated in maternal and fetal serum, and the impact of other bile acids on fetal arrhythmias has not been established
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