Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Abstract

In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca ] ), and sphingosine-1-phosphate (S1P)-receptor via Gα -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca ] , and S1P-Gα -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gα inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl -induced [Ca ] dynamic alteration. Pharmacological inhibition of the Gα -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl detrimental effects, except for cell viability and [Ca ] . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl -induced [Ca ] dynamic changes. We conclude that UDCA cardioprotection against CoCl -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gα -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.

The impact of ursodeoxycholic acid treatment on myocardial performance index in the obstetric cholestasis cases

“…[14,17] On the other hand, in addition to the conduction, it also decreases the activation of p53 and HIF-1 alpha activation which are the factors responsible for tissue damage during the hypoxia in cardiac myocytes. [18] In consistent with the literature, we found in our study that the prolonged fetal AV conduction time associated with the obstetric cholestasis was shortened by UDC treatment. [15] MPI shows both systolic and diastolic cardiac functions.…”

Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart

“…Taurocholic acid is a taurine-conjugated hydrophobic BA that has been reported as a partial agonist of the muscarinic M2 receptor (Gαi-coupled receptor), which induces arrhythmia in cultured CMs [62]. In agreement with Sheikh Abdul Kadir et al [62], Mohamed et al [93] reported that UDCA maintains the normal intracellular [Ca 2+ ] i dynamics against hypoxic condition, which is also mediated by Gαi-coupled receptor. Gorelik et al [94] showed that UDCA protects the heart from TC-induced arrhythmias by improving contraction and calcium dynamic changes in CMs.…”

“…In addition, S1P3 receptors are expressed in the heart, and its activation results in bradycardia [127]. Mohamed et al [93] reported that UDCA’s protection of CMs against hypoxia could be mediated partly by S1P1 receptor. The study suggested that cardioprotection of UDCA was observed to be similar to FTY720 (S1P receptor agonist) in inhibiting the lethal effect of hypoxia through inhibition of HIF-1α and p53 protein and restoration of normal [Ca 2+ ] i in hypoxic CMs [93].…”

“…Mohamed et al [93] reported that UDCA’s protection of CMs against hypoxia could be mediated partly by S1P1 receptor. The study suggested that cardioprotection of UDCA was observed to be similar to FTY720 (S1P receptor agonist) in inhibiting the lethal effect of hypoxia through inhibition of HIF-1α and p53 protein and restoration of normal [Ca 2+ ] i in hypoxic CMs [93]. As demonstrated by multiple pieces of evidence, BAs activate various pathways, as reviewed in other sections, and UDCA is suggested to activate Gαi-coupled receptor-dependent pathways and/or Gαi-coupled receptor-independent pathways in mediating cellular response.…”

Bile Acid Signaling and Cardioprotection

“…This leads to p53 translocation into the cytoplasm which promotes its degradation by the proteasome. Mohamed et al, [123] has shown that UDCA inhibits the upregulation of p53 and hif-1α in hypoxic cardiomyocytes. HIF-1 is used to target many genes such as p53, VEGF, nitric oxide synthase, PDK1 in mediating tumor metastasis, angiogenesis, energy metabolism and metabolic adaptation.…”