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Protective and hypertrophic effects of cardiotrophin-1 in the heart

Railson, Julia Elizabeth; (2000) Protective and hypertrophic effects of cardiotrophin-1 in the heart. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Cardiotrophin-l (CT-1) is a member of the interleukin-6 family of cytokines that was first isolated based on its ability to cause hypertrophy in cardiac myocytes. Hypertrophy is an initially compensatory response in the heart defined by enlargement of cells without division and reactivation of foetal genes. Chronic hypertrophy can be detrimental and may lead to heart failure. CT-1 is also a potent survival factor in cardiac myocytes and increases levels of cardioprotective heat shock protein 90 (hsp90). The subject of this thesis is an investigation of the mechanisms involved in cardiac protection, hypertrophy and heat shock protein induction by CT-1. CT-1 increased hsp90 levels independently of RNA synthesis and without an increase in hsp90 mRNA level or activation of the promoter. This implies that CT-1 is acting via a post-transcriptional mechanism to increase hsp90 protein levels. Treatment with CT-1 prior to a stressful stimulus such as heat shock caused a reduction in the amount of hsp90 and hsp70 produced in response to the stress. The possible mechanisms for this novel antagonistic effect are discussed. The protective effect of CT-1 is dependent on the p42/p44 Mitogen activated protein kinase (p42/p44 MAPK) pathway and the hypertrophic effect is independent from this pathway. It is demonstrated that the hypertrophic effect of CT-1 is dependent on the signal transducer and activator of transcription 3 (STAT3) pathway. The hypertrophic effect of CT-1 can therefore be blocked by inhibition of the STAT3 pathway while leaving the protective effect intact. This divergence in the signalling pathways stimulated by CT-1 may prove important if CT-1 were to be developed as a cardioprotective agent for use in the clinical setting. Heat shock protein 56 (hsp56) (also known as FK506 binding protein 59) was shown to increase at both the mRNA and protein level in response to CT-1 treatment. Subsequent studies using herpes viral vectors or plasmid transfection to over express heat shock proteins in cardiac cells showed that elevated levels of hsp56 caused hypertrophy. Additionally, transfection of antisense hsp56 DNA inhibited the hypertrophic effect of CT- 1. These data suggest that hsp56 is involved in the hypertrophic response to CT-1. Urocortin is a peptide hormone of the Corticotrophin releasing factor family, which is cardioprotective via the same pathway as CT-1. It is shown here that urocortin is also hypertrophic, but via a distinct pathway to CT-1.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Protective and hypertrophic effects of cardiotrophin-1 in the heart
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Cardiotriphin-1
URI: https://discovery.ucl.ac.uk/id/eprint/10097278
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