Mechanism of ursodeoxycholic acid (UDCA) cardioprotection against hypoxia / Anis Syamimi Mohamed
Ursodeoxycholic acid (UDCA) is the most hydrophilic bile acid and is widely used to treat liver diseases especially in cholestasis. Recently, UDCA is shown to have a potential effect in treating a cardiovascular disease which is an alternative to the current drugs that contains severe side effect. S...
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| Format: | Thesis |
| Language: | English |
| Published: |
2016
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| Subjects: | |
| Online Access: | https://ir.uitm.edu.my/id/eprint/62269/1/62269.pdf https://ir.uitm.edu.my/id/eprint/62269/ |
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| Summary: | Ursodeoxycholic acid (UDCA) is the most hydrophilic bile acid and is widely used to treat liver diseases especially in cholestasis. Recently, UDCA is shown to have a potential effect in treating a cardiovascular disease which is an alternative to the current drugs that contains severe side effect. Studies have demonstrated that UDCA action is mediated by the sphingosine-1-phosphate (S1P) receptor in hepatocytes, however, not in heart. Furthermore, the mechanism of UDCA cardioprotection is still poorly understood. Therefore, this study was conducted to elucidate the mechanism of UDCA cardioprotection by using an in vitro hypoxic cardiomyocytes (CMs) model. CMs were isolated from newborn rats (0-2 days) and hypoxia was induced using chamber and CoCl2. Cells were treated with UDCA (pre-UDCA and post-UDCA) and co-treated with either FTY720 (S1P receptor agonist) and PTX (Gαi inhibitor). The treated cells were subjected to proliferation assay (MTS assay), gene expression, protein expression (Western blot and immunofluorescence) and calcium imaging
(loaded with Fluo-4). The data were analyzed by using the Sample Paired/Unpaired TTest and One-way ANOVA. The findings of study show UDCA abolished the effect of chamber (Mean ± SEM; 55 % ± 7, p < 0.05) and CoCl2-induced hypoxia (49 ± 4%, p < 0.05) on cell viability [UDCA-chamber (106% ± 2) and UDCA-CoCl2 (94% ± 2, p < 0.05)]. No significant differences were observed in pre-UDCA and post-UDCA in hypoxic CMs (p > 0.05). The protective effect of UDCA was also observed in HIF-1α and p53 protein expression (UDCA-CoCl2: 0.5387 ± 0.0087 vs CoCl2 only: 0.8180 ± 0.0454, p < 0.05) where both HIF-1α and p53 protein were downregulated. Apart from that, no involvement of HIF-1α, eNOS, NF-κB, FXR and BNIP3 gene were observed in this study. In addition, UDCA (0.95 ± 0.04) was shown to inhibit the alteration of [Ca2+]i observed in CoCl2-induced hypoxia cells (0.28 ± 0.03, p < 0.05). Treatment with PTX (Gαi inhibitor) partially inhibits the effect of UDCA on cell survival, but full inhibition of UDCA effect was observed in [Ca2+]i . The inhibition of Gαi-coupled receptor pathways on HIF-1α and p53 protein expressions by PTX seems to further activate the effect of UDCA. Meanwhile, FTY720 shows the similarity of action with
UDCA in cell viability, [Ca2+]i , HIF-1α and p53 protein expression. In conclusion, the current data suggest that UDCA could partially be mediated by Gαi-coupled receptordependent and Gαi-coupled receptor-independent pathways in cardioprotection mechanism against hypoxia. Furthermore, this study provides an insight of UDCA mechanism for cardioprotection in treating heart disease. |
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