Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5

Ibrahim, Effendi; Diakonov, Ivan; Arunthavarajah, Dulasi; Swift, Teresa; Goodwin, M.; McIlvride, Saraid; Nikolova, Vanya; Williamson, Catherine; Gorelik, Julia

doi:10.1038/s41598-018-25569-4

Cited by 59 publications

(64 citation statements)

References 39 publications

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“…Recently, BAs have been recognized as signaling molecules that can integrate with their receptors, including the nuclear Farnesoid X Receptor (FXR) and Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5). TGR5 is known to be expressed by multiple organ systems such as the liver, the renal system, brain, heart and the retinas . The roles for TGR5 in regulating metabolic homeostasis have been well documented.…”

Section: Introductionmentioning

confidence: 99%

“…TGR5 is known to be expressed by multiple organ systems such as the liver, the renal system, brain, heart and the retinas. [8][9][10][11][12] The roles for TGR5 in regulating metabolic homeostasis have been well documented. In the last several years, research on BAs and their receptors has been extended to their possible roles on the regulation of endothelium functions.…”

Section: Introductionmentioning

confidence: 99%

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TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

et al. 2020

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Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus‐induced microvascular dysfunction in retinas is largely unknown. Herein, enzyme‐linked immunosorbent assay was used for analyzing bile acid (BA) profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin (STZ)‐induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion, and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho‐associated coiled‐coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways. Here we show that bile acids were downregulated during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes‐induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF‐α on endothelial cell proliferation, migration, and permeability in vitro. In contrast, knockdown of TGR5 by siRNA aggravated TNF‐α‐induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF‐α stimulation. Taken together, our findings suggest that insufficient BA signaling plays an important pathogenic role in the development of DR. Upregulation or activation of TGR5 may inhibit RhoA/ROCK‐dependent actin remodeling and represent an important therapeutic intervention for DR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

et al. 2020

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“…[8][9][10][11][12][13]22,23 On rat models and in in vitro studies, it has been shown that TBAs, especially taurocholic acids, can cause sinoatrial node dysfunction, desynchronized cardiomyocyte contraction, and alteration in atrioventricular conduction system due to changes in calcium dynamics. 11,12,[24][25][26][27][28] Also, Ibrahim et al demonstrated that bile acids can play a role as partial agonists of muscarinic receptor type 2 and lead to reducing the contraction rate of neonatal cardiomyocytes. 27 Considering the data obtained, it is suggested that ICP-associated fetal arrhythmia and IUFD can be the results of the accumulation of elevated bile acids in fetal cardiac cells.…”

Section: Discussionmentioning

confidence: 99%

“…11,12,[24][25][26][27][28] Also, Ibrahim et al demonstrated that bile acids can play a role as partial agonists of muscarinic receptor type 2 and lead to reducing the contraction rate of neonatal cardiomyocytes. 27 Considering the data obtained, it is suggested that ICP-associated fetal arrhythmia and IUFD can be the results of the accumulation of elevated bile acids in fetal cardiac cells. Accordingly, in this study, ICP groups were divided into two sections, mild and severe ICP, with reference to bile acid levels, and the data showed that fetal mechanical PR interval was longer in the severe ICP group than in the mild ICP group (p < 0.05).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Mechanical Fetal PR Interval in Intrahepatic Cholestasis of Pregnancy and Its Relationship with the Severity of the Disease

et al. 2019

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Objective To investigate the fetal atrioventricular conduction system in intrahepatic cholestasis of pregnancy (ICP) by measuring the fetal mechanical PR interval and to explore the significance of predicting the severity of the disease. Study Design Forty pregnant women diagnosed with ICP, classified as severe and mild, and 40 healthy pregnant women participated in the study. Fetal mechanical PR interval was calculated, and fetal mechanical PR interval and neonatal outcome were compared between the groups. The relationship between the mechanical PR interval and the severity of ICP was analyzed. Results The fetal mechanical PR interval was significantly longer in the ICP group than in the control group (p < 0.005). Likewise, laboratory parameters such as transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and total bilirubin levels were significantly higher in the ICP group (p < 0.005).There were no statistically significant differences in the fetal complications. There was a positive correlation between the severity of disease and fetal PR interval. Conclusion A prolonged fetal mechanical PR interval in fetuses of mothers with ICP was demonstrated in this study. It was also shown that there was a positive correlation between fetal PR interval and severity of the disease. The study concluded that fetal mechanical PR interval measurement can be used to predict the severity of disease in ICP.

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“…Those effects were mediated by M2 muscarinic receptor [41]. Similarly, Ibrahim et al [42] showed that conjugated bile acids action was mediated by M2 muscarinic receptor and not sphingosine 1 phosphate 2 receptor.…”

Section: Muscarinic Receptormentioning

confidence: 94%

Bile Acid Signaling and Cardioprotection

Hanafi¹,

As²,

Sh³

2018

Preprint

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Bile acids (BA) are classically known as an agent important in lipid absorption and cholesterol metabolism. Nowadays, BAs have been found to be involved in various cellular signaling pathways such as protein kinase cascades, cyclic AMP (cAMP) synthesis and calcium mobilization. In addition, they have also been shown to regulate glucose and energy homeostasis. Bile acids are ligands for several nuclear hormone receptors, including FXR. Recently, muscarinic receptor and TGR5, G-protein-coupled receptor (GPCR), have been suggested to play a role in bile acid activity which is independent of nuclear hormone receptors. Moreover, BAs have also been studied in other GPCR associated pathways, namely sphingosine-1-posphate and glucagon receptor. Hydrophobic bile acids have been proven to affect heart rate and its contraction. Elevated bile acids are associated with arrhythmias in adults and fetal heart. Altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase of serum bile acid concentrations. In contrast, the most hydrophilic BA known as ursodeoxycholic acid has been found beneficial in improving peripheral blood flow in chronic heart failure patients and protecting heart against reperfusion injury.

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Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5

Cited by 59 publications

References 39 publications

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

Assessment of Mechanical Fetal PR Interval in Intrahepatic Cholestasis of Pregnancy and Its Relationship with the Severity of the Disease

Bile Acid Signaling and Cardioprotection

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