Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.631802
Title: Regulation of cardiac ischaemia/reperfusion injury or hypertrophy by interferon-gamma and cardiotrophin-1 signalling pathways
Author: Carroll, C. J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2008
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Abstract:
Cardiac ischaemia/reperfusion (I/R)-injury and hypertrophy are two causes of heart failure. The molecular pathways that regulate these processes include those that are stimulated by the cytokines, interferon-gamma (IFNy) and cardiotrophin-1 (CT-1). This thesis describes the investigation of components of the IFNy or CT-1 signalling pathways and their regulation of I/R-injury or hypertrophy. The transcription factor, signal transducer and activator of transcription 1 (STAT1), is the primary mediator of the IFNy signalling pathway and promotes apoptosis of cardiac cells following I/R-injury or stimulation with IFNy. It is unclear what contribution the caspase-8 and caspase-9 apoptotic pathways have in STAT1 mediated I/R-injury and IFNy induced apoptosis. Therefore, to investigate this relationship, constructs conditionally overexpressing specific caspase inhibitors were used to generate transgenic mice with inactivated caspase-8 or -9 pathways. STAT1 and the transcription factor p53 proteins are known to associate and this interaction has been demonstrated to be necessary for the maximal activation of distinct p53 target genes. STAT1 and p53 double knockout mice were generated to further investigate the role of these proteins in I/R-injury. A proteomic approach was used to identify proteins regulated by STAT1 and/or p53 in the heart where the expression of the cytokine, interleukin-6, was regulated by STAT1 and p53. The CT-1 cytokine has cardioprotective and hypertrophic effects. CT-1 expression is induced by another cardioprotective cytokine, urocortin. The mechanism by which urocortin protects the heart from I/R-injury is not fully understood, however, prevention of mitochondrial damage has been shown to be involved. In this study the protective effect of urocortin was shown to involve the mitochondrial permeability transition pore. Furthermore, the hypertrophic effect of CT-1 in cultured cardiac cells has been shown to be dependent on induction of heat shock protein 56 (hsp56). Transgenic mice overexpressing hsp56 were generated to test the cardioprotective and hypertrophic effects of hsp56 in vivo. Taken together, the data presented here demonstrate clearly that a number of key molecules regulate cardiac (patho)physiology in vivo. Targeting these signalling pathways may provide novel routes for therapeutic intervention in heart disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.631802  DOI: Not available
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