Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi

Ursodeoxycholic acid (UDCA), the most hydrophilic bile acid is used as a therapeutic agent in liver related diseases and to eliminate hydrophobic bile acid induced apoptosis in liver. Recently, studies suggested the potential used of UDCA in treating heart related diseases. UDCA is reported cardiopr...

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Main Author:	Hanafi, Noorul Izzati
Format:	Thesis
Language:	English
Published:	2017
Subjects:	Medical education Medical schools Research Administration
Online Access:	https://ir.uitm.edu.my/id/eprint/38895/3/38895.pdf
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spelling	my-uitm-ir.388952024-08-02T03:08:24Z Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi 2017-02 Hanafi, Noorul Izzati Medical education. Medical schools. Research Administration Ursodeoxycholic acid (UDCA), the most hydrophilic bile acid is used as a therapeutic agent in liver related diseases and to eliminate hydrophobic bile acid induced apoptosis in liver. Recently, studies suggested the potential used of UDCA in treating heart related diseases. UDCA is reported cardioprotective against the development of ischemia. However, the mechanism of action in UDCA-cardioprotection is not clearly understood. Therefore, this study aimed to determine the anti-apoptotic mechanisms of UDCA on cardioprotection using an in vitro hypoxic model of neonatal rat cardiomyocytes. Rat heart from newborn (0-2 days old) was isolated for primary cell culture of cardiomyocytes. Hypoxia was induced by using C0CI2 and hypoxic chamber. Cardiomyocytes were incubated with UDCA (pre-UDCA and post-UDCA) and coincubated with FTY720 (SIP receptor agonist), PTX (Ga; inhibitor). The treated cardiomyocytes were subjected for proliferation assay (MTS assay), beating assessment assay, protein expression (aSMase and nSMase, Hif-la, caspase-3 and caspase-9, ERK and Akt), ROS generation assay and gene expression {Hif-la, smpdl, smpd2, caspase-3, caspase-9). The data were analyzed by using sample paired t-test and One-way ANOVA. MTS assay revealed that UDCA was not toxic to cardiomyocytes even at high concentration (250 urn). Results showed that C0CI2 activates Hif-la expression, reduces cell viability; reduce beating rate, upregulates nSMase protein, increases ROS production, downregulates ERK and Akt protein expression. Interestingly, pre-UDCA treatment significantly abolished the negative effects of C0CI2 on cell viability, beating rate, ROS production, ERK and Akt expression in cardiomyocytes. Treatment with PTX partially inhibits the protection of UDCA against C0CI2 negatives effects on beating rate of cardiomyocytes. Meanwhile, FTY720 showed similarity with UDCA action in downregulating smpdl gene expression and upregulates caspase-9 gene expression. In conclusion, the current data suggests that UDCA mechanism is mediated partially through Gdi-coupled receptor dependent and independent pathways in protecting cardiomyocytes against hypoxia. This study provides an insight of anti-apoptotic mechanism of UDCA on hypoxic cardiomyocytes. 2017-02 Thesis https://ir.uitm.edu.my/id/eprint/38895/ https://ir.uitm.edu.my/id/eprint/38895/3/38895.pdf text en public masters Universiti Teknologi MARA (UiTM) Faculty of Medicine Sheikh Abdul Kadir, Siti Hamimah
institution	Universiti Teknologi MARA
collection	UiTM Institutional Repository
language	English
advisor	Sheikh Abdul Kadir, Siti Hamimah
topic	Medical education Medical schools Research Administration
spellingShingle	Medical education Medical schools Research Administration Hanafi, Noorul Izzati Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
description	Ursodeoxycholic acid (UDCA), the most hydrophilic bile acid is used as a therapeutic agent in liver related diseases and to eliminate hydrophobic bile acid induced apoptosis in liver. Recently, studies suggested the potential used of UDCA in treating heart related diseases. UDCA is reported cardioprotective against the development of ischemia. However, the mechanism of action in UDCA-cardioprotection is not clearly understood. Therefore, this study aimed to determine the anti-apoptotic mechanisms of UDCA on cardioprotection using an in vitro hypoxic model of neonatal rat cardiomyocytes. Rat heart from newborn (0-2 days old) was isolated for primary cell culture of cardiomyocytes. Hypoxia was induced by using C0CI2 and hypoxic chamber. Cardiomyocytes were incubated with UDCA (pre-UDCA and post-UDCA) and coincubated with FTY720 (SIP receptor agonist), PTX (Ga; inhibitor). The treated cardiomyocytes were subjected for proliferation assay (MTS assay), beating assessment assay, protein expression (aSMase and nSMase, Hif-la, caspase-3 and caspase-9, ERK and Akt), ROS generation assay and gene expression {Hif-la, smpdl, smpd2, caspase-3, caspase-9). The data were analyzed by using sample paired t-test and One-way ANOVA. MTS assay revealed that UDCA was not toxic to cardiomyocytes even at high concentration (250 urn). Results showed that C0CI2 activates Hif-la expression, reduces cell viability; reduce beating rate, upregulates nSMase protein, increases ROS production, downregulates ERK and Akt protein expression. Interestingly, pre-UDCA treatment significantly abolished the negative effects of C0CI2 on cell viability, beating rate, ROS production, ERK and Akt expression in cardiomyocytes. Treatment with PTX partially inhibits the protection of UDCA against C0CI2 negatives effects on beating rate of cardiomyocytes. Meanwhile, FTY720 showed similarity with UDCA action in downregulating smpdl gene expression and upregulates caspase-9 gene expression. In conclusion, the current data suggests that UDCA mechanism is mediated partially through Gdi-coupled receptor dependent and independent pathways in protecting cardiomyocytes against hypoxia. This study provides an insight of anti-apoptotic mechanism of UDCA on hypoxic cardiomyocytes.
format	Thesis
qualification_level	Master's degree
author	Hanafi, Noorul Izzati
author_facet	Hanafi, Noorul Izzati
author_sort	Hanafi, Noorul Izzati
title	Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
title_short	Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
title_full	Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
title_fullStr	Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
title_full_unstemmed	Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi
title_sort	anti-apoptotic mechanism of ursodeoxycholic acid (udca) on hypoxic cardiomyocytes / noorul izzati hanafi
granting_institution	Universiti Teknologi MARA (UiTM)
granting_department	Faculty of Medicine
publishDate	2017
url	https://ir.uitm.edu.my/id/eprint/38895/3/38895.pdf
_version_	1811768624392699904

Anti-apoptotic mechanism of ursodeoxycholic acid (UDCA) on hypoxic cardiomyocytes / Noorul Izzati Hanafi

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