Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.779591
Title: The role of Pontin in stress-induced cardiac hypertrophy
Author: Bui, Thuy
ISNI:       0000 0004 7965 2860
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Abstract:
Cardiovascular disease (CVD) with end-stage heart failure is the leading cause of death globally with increasing prevalence in the aging populations. In response to pathological stress such as chronic hypertension, increased blood volume triggers heart enlargement to initially adapt to increased demand for cardiac performance. However, prolonged cardiac hypertrophy can trigger adverse modifications in the heart such as increased cardiac fibrosis, oxidative stress, cardiomyocyte death, cardiac arrhythmia and finally heart failure. The inhibition of pathological cardiac hypertrophy therefore presents as a promising therapeutic strategy to prevent heart failure progression. In the attempts of identifying therapeutic targets for heart failure management, several oncogenes have been recognised as the regulators of pathological cardiac hypertrophy. In this study, we hypothesised that Pontin, commonly known as an oncogene, was involved in regulating cardiac responses to hypertrophic stimuli. This study employed two mouse models i.e., Pontin global heterozygous knockout and cardiomyocyte-specific Pontin expression to investigate the possible in vivo functions of Pontin in regulating cardiac responses under chronic Angiotensin II infusion. Cardiac characterisation has revealed that the lack of Pontin was associated with increased cardiomyocyte death, oxidative stress and excessive autophagy in the heart during stress conditions. Meanwhile, Pontin overexpression could alleviate these adverse modifications in the heart under the same stimuli. Mechanistic analysis has shown that Pontin could regulate autophagy induction through the mTORC1 complex. The lack of Pontin or its ATPase activity could result in reduced mTORC1 function and subsequently increased autophagy induction in cardiomyocytes. Additionally, the findings from this study also indicated the adverse role of excessive cardiomyocyte autophagy in pathological cardiac hypertrophy. Therefore, the manipulation of cardiac autophagy downstream of Pontin or the mTORC1 complex could become a promising strategy to prevent pathological cardiac hypertrophy and possibly heart failure.
Supervisor: Wang, Xin ; Oceandy, Delvac Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.779591  DOI: Not available
Keywords: Pontin ; RUVBL1 ; cardiac hypertrophy ; angiotensin II ; autophagy ; mTOR
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