Characterisation of cardiac function and RUNX expression in two separate models of heart disease

Foote, Kirsty K. (2012) Characterisation of cardiac function and RUNX expression in two separate models of heart disease. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Heart disease is the leading cause of death worldwide. Despite considerable progress in the prevention and treatment of heart disease it remains a highly prevalent source of patient morbidity and mortality. The heart has the ability to change in shape, size, structure and function in response to adverse stimuli in a process known as cardiac remodelling which is intended to be an adaptive response initially but can become detrimental leading to eventual heart failure (HF). The mechanisms underlying the progression from remodelling to HF remain poorly understood. Remodelling in the heart is known to be associated with alterations in cardiac gene expression for which transcription factors play a significant role. It has been reported that the RUNX family of transcription factors which play important roles in developmental pathways, have been increasingly implicated in disease and in tissue injury. One member of this family of transcription factors, RUNX1, has been shown to be up-regulated in heart tissue taken from human patients with MI. Despite this knowledge, a precise quantitative measure of the altered expression of Runx in the heart in terms of regional and temporal changes using an animal model has not been previously explored. Therefore the aim of the work presented in this thesis was to investigate the altered expression of the Runx genes in two different experimental animal models of heart disease: a mouse model of myocardial infarction (MI) and a rat model of hypertension and altered left ventricular (LV) mass to assess the changes in Runx expression in response to the different cardiac disease types. For this study a mouse model of MI was developed using the well-established coronary artery ligation (CAL) method and the phenotype of this model was characterised at different time points by assessing survival trends, performing in vivo functional measurements (pressure-volume (PV) loop methodology and electrocardiograms) with assessment of structural alterations of remodelling using histological and morphometric measurements. The model was found to exhibit many of the clinical features consistent not only with other published murine model data but also those of human MI. The mouse MI model was then used to measure Runx gene expression in the hearts using real time quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry (IHC) methods. This was to assess whole heart and regional expression differences, how expression levels change over time as the MI develops, assessment of expression patterns of the different Runx gene members and exploration of potential links with Runx expression and possible functional relevance to the heart. In the mouse model, Runx genes were found to be up-regulated in response to MI with highest levels confined to the areas within and around the infarct and peri-infarct region by 4 weeks post-MI extending into the remote regions by 8 weeks. Runx levels were found to be highest in the hearts with the greatest dysfunction. The second model of heart disease for assessing changes in Runx was a rat model of hypertension, with congenic sub-strains of this model showing altered LV mass also tested. The congenic rat strains were specifically bred models of rat with a chromosome 14 substitution. This contained a quantitative trait locus (QTL) from either normotensive or hypertensive strains for genes associated with LV mass. These models were analysed using in vivo PV methodology to assess function without influence from blood pressure (BP) loading conditions (to assess whether the QTL is BP-dependent) and structural remodelling in the form of cardiac fibrosis was measured histologically. The data revealed enhanced systolic function with diastolic dysfunction and cardiac fibrosis in hypertensive animals consistent with other published models. The chromosome 14 congenic rat strains showed a BP-independent diastolic dysfunction or improved function linked to cardiac fibrosis. Furthermore, in contrast to the MI model, the levels of Runx1 were significantly down-regulated in the rat models of hypertension and altered LV mass indicating potential differences in the triggers for altered expression between volume-overload versus pressure-overload models of heart disease. Overall this thesis has shown the altered expression of Runx genes in two different animal models of heart disease which has not been previously explored and indicates potential for future investigation into the functional significance of Runx in the heart during disease.

Item Type:	Thesis (PhD)
Qualification Level:	Doctoral
Keywords:	Myocardial infarction, hypertension, remodelling, Runx
Subjects:	Q Science > QP Physiology
Colleges/Schools:	College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name:	Loughrey, Dr. Christopher
Date of Award:	2012
Embargo Date:	13 November 2015
Depositing User:	Miss Kirsty Katrina Foote
Unique ID:	glathesis:2012-3746
Copyright:	Copyright of this thesis is held by the author.
Date Deposited:	21 Nov 2012
Last Modified:	10 Dec 2012 14:10
URI:	http://theses.gla.ac.uk/id/eprint/3746

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