The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts

Schultz, Francisca; Hasan, Alveera; Alvarez-Laviada, Anita; Miragoli, Michele; Bhogal, Navneet; Wells, Sarah; Poulet, Claire; Chambers, Jenny; Williamson, Catherine; Gorelik, Julia

doi:10.1016/j.pbiomolbio.2016.01.003

Cited by 38 publications

(43 citation statements)

References 55 publications

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“…CA has been shown to stimulate myometrial oxytocin receptor expression and to induce preterm labour when infused into sheep . Furthermore, addition of CA to the culture medium of rodent and human in vitro models of the fetal heart resulted in arrhythmia, suggesting that this BA causes potentially fatal fetal arrhythmia . Therefore, the finding of an association between severe ICP (with maternal serum BA ≥40 micromol/l) and fetal complications has influenced clinical practice and increased the focus on monitoring of BA concentrations .…”

Section: Discussionmentioning

confidence: 99%

Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study

Manna

Ovadia

Lövgren‐Sandblom

et al. 2019

BJOG

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Objective To evaluate enzymatic total serum bile acid quantification as a monitoring strategy for women with intrahepatic cholestasis of pregnancy (ICP) treated with ursodeoxycholic acid (UDCA). Design Cohort.Setting One UK university hospital.Population 29 ICP cases treated with UDCA.Methods Serial samples were collected prospectively throughout gestation. Total serum bile acids were measured enzymatically and individual bile acids by high-performance liquid chromatographytandem mass spectrometry. Data were log-transformed and analysed with random effects generalised least square regression.Main outcome measures The relationship between enzymatic total bile acid measurements and individual bile acid concentrations after UDCA treatment. ResultsIn untreated women, cholic acid was the principal bile acid (51%) and UDCA concentrations were <0.5%, whereas UDCA constituted 60% (IQR 43-69) of serum bile acids following treatment and cholic acid fell to <20%. Changes in the total bile acid measurement reflected similar alterations in the concentrations of the pathologically elevated bile acids, e.g. a twofold increase in enzymatic total bile acids is accompanied by approximately a two-fold increase in cholic acid and chenodeoxycholic acid at most UDCA doses (P < 0.001). Most of the effects of UDCA on cholic acid occur in the first week of treatment (60% relative reduction, P = 0.025, 95% CI 0.2-0.9, from 10 micromol/l (4.7-17.6) to 3.5 micromol/l (1.4-7.5).Conclusion Ursodeoxycholic acid becomes the main component of the bile acid measurement after treatment. Enzymatic total bile acid assays are good predictors of both cholic acid and chenodeoxycholic acid, the primary bile acids that are raised prior to treatment.Keywords Bile acid assay, cholestasis, pregnancy, ursodeoxycholic acid.Tweetable abstract Ursodeoxycholic acid constitutes approximately 60% of the bile acid measurement and reduces pathological cholic acid in treated women.Please cite this paper as: Manna LB, Ovadia C, L€ ovgren-Sandblom A, Chambers J, Begum S, Seed P, Walker I, Chappell LC, Marschall H-U, Williamson C. Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study.

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Section: Discussionmentioning

confidence: 99%

Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study

Manna

Ovadia

Lövgren‐Sandblom

et al. 2019

BJOG

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“…Isolation of neonatal rat ventricular cardiomyocytes and myofibroblasts from 1-2-d-old Sprague-Dawley rats was done in accordance with the guidelines of the Home Office Animal (Scientific Procedures) Act of 1986 of the United Kingdom. Cardiomyocytes and myofibroblasts were isolated and cultured as previously described (31). Monocultures of cardiomyocytes or myofibroblasts were seeded into MatTek dishes (13 cm 2 ; MatTek, Ashland, MA, USA) or plastic-bottom dishes (35 mm, CytoOne; USA Scientific, Ocala, FL, USA).…”

Section: Neonatal Rat Cells Used For Contact Motility Studiesmentioning

confidence: 99%

“…For the coculture experiments, cardiomyocytes were also plated in dishes, with myofibroblasts seeded on top on the subsequent day. The myofibroblasts were detached as previously described (31), spun, and resuspended in 1 ml HBSS per 1 million cells. The myofibroblasts were then labeled by incubating for 20 min at 37°C and 1% CO 2 with either Vybrant DiI (excitation/emission: 549/565 nm; Thermo Fisher Scientific, Waltham, MA, USA) or WGA-488 (wheat germ agglutinin-488, excitation/emission: 495/519 nm; Thermo Fisher Scientific) for recognition afterward.…”

Section: Neonatal Rat Cells Used For Contact Motility Studiesmentioning

confidence: 99%

Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43

et al. 2019

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Healthy cardiomyocytes are electrically coupled at the intercalated discs by gap junctions. In infarcted hearts, adverse gap‐junctional remodeling occurs in the border zone, where cardiomyocytes are chemically and electrically influenced by myofibroblasts. The physical movement of these contacts remains unquantified. Using scanning ion conductance microscopy, we show that intercellular contacts between cardiomyocytes and myofibroblasts are highly dynamic, mainly owing to the edge dynamics (lamellipodia) of the myofibroblasts. Decreasing the amount of functional connexin‐43 (Cx43) at the membrane through Cx43 silencing, suppression of Cx43 trafficking, or hypoxia‐induced Cx43 internalization attenuates heterocellular contact dynamism. However, we found decreased dynamism and stabilized membrane contacts when cellular coupling was strengthened using 4‐phenylbutyrate (4PB). Fluorescent‐dye transfer between cells showed that the extent of functional coupling between the 2 cell types correlated with contact dynamism. Intercellular calcein transfer from myofibroblasts to cardiomyocytes is reduced after myofibroblast‐specific Cx43 down‐regulation. Conversely, 4PB‐treated myofibroblasts increased their functional coupling to cardiomyocytes. Consistent with lamellipodia‐mediated contacts, latrunculin‐B decreases dynamism, lowers physical communication between heterocellular pairs, and reduces Cx43 intensity in contact regions. Our data show that heterocellular cardiomyocyte‐myofibroblast contacts exhibit high dynamism. Therefore, Cx43 is a potential target for prevention of aberrant cardiomyocyte coupling and myofibroblast proliferation in the infarct border zone.—Schultz, F., Swiatlowska, P., Alvarez‐Laviada, A., Sanchez‐Alonso, J. L., Song, Q., de Vries, A. A. F., Pijnappels, D. A., Ongstad, E., Braga, V. M. M., Entcheva, E., Gourdie, R. G., Miragoli, M., Gorelik, J. Cardiomyocyte–myofibroblast contact dynamism is modulated by connexin‐43. FASEB J. 33, 10453–10468 (2019). http://www.fasebj.org

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“…Their initial report revealed that taurocholate altered calcium dynamics which led to loss of synchronous beating of cardiomyocytes. The same group showed that taurocholic acid was responsible for reduced contractility and pacemaker activity while ursodeoxycholic acid protected against reentrant arrhythmias by modulating potassium conductance …”

Section: Bile Acids and Cardiovascular Functionmentioning

confidence: 99%

“…The same group showed that taurocholic acid was responsible for reduced contractility and pacemaker activity 61 while ursodeoxycholic acid protected against reentrant arrhythmias by modulating potassium conductance. 62,63 Due to the difficulties of conducting studies in the setting of ICP, such conclusions are mainly based on cell-cultures and animal models with few studies looking into the arrhythmogenic effects of BA in humans. 64 Rainer et al 65 showed that taurocholic acid-induced concentration-dependent arrhythmia in human atrial myocardium and noted an association between atrial fibrillation and higher serum levels of nonursodeoxycholic bile acid conjugates and low levels of ursodeoxycholic acid conjugates in 250 patients.…”

Section: Cardiac Effectsmentioning

confidence: 99%