The effect of hypoxia and reoxygenation on STAT3 regulation in potential cardiomyocyte models

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Evans, Emma Louise (2012) The effect of hypoxia and reoxygenation on STAT3 regulation in potential cardiomyocyte models. PhD thesis, University of Nottingham.

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Abstract

Cardiomyocyte apoptosis is an important contributory factor towards the progression of ischaemic heart disease. Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor has that been implicated in normal heart development and function. Most interestingly, STAT3 also appears to play a role in cardioprotection, including hypoxic preconditioning. In this thesis the levels and activities of ST A T3 were measured in response to hypoxic insult in primary rat cardiomyocytes (RCMs) and two cardiomyocyte cell lines (H9c2 and P19CL6 cells). P19CL6 cells were extremely sensitive to hypoxia-induced apoptosis whereas RCMs and H9c2 cells were highly resistant.

Apoptosis in P19CL6 cells correlated with loss of STAT3 DNA binding, which was preceded by serine phosphorylation and followed by loss of tyrosine phosphorylation. Treatment with LIF partially protected P19CL6 cells from hypoxia-induced apoptosis, as did exogenous expression of STAT3 but not a redox-insensitive ST AT3 mutant (STAT3C3s ). Moreover, STAT3 expression rescued mitochondrial ATP production during hypoxia whereas the redox-insensitive mutant did not. These data indicate that the contribution of STAT3 to cardiomyocyte survival under hypoxic stress involves the maintenance of mitochondrial function by a redox-dependent mechanism.

Understanding how STAT3 is regulated in cardiomyocytes will be important for the development of therapeutic approaches for ischaemic heart disease in the future.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Shaw, P.E.
Vinkemeier, U.
Keywords: Cellular signal transduction, STAT Transcription Factors, Cardiomyocyte apoptosis
Subjects: W Medicine and related subjects (NLM Classification) > WG Cardiocascular system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Biomedical Sciences
Item ID: 28293
Depositing User: Blore, Mrs Kathryn
Date Deposited: 02 Feb 2015 12:48
Last Modified: 19 Dec 2017 03:26
URI: https://eprints.nottingham.ac.uk/id/eprint/28293

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