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Title: The role of PMCA1 in post-myocardial infarction remodelling
Author: Stankovikj, Vera
ISNI:       0000 0004 7429 6991
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Coronary artery disease and its main consequence - myocardial infarction (MI) - are the UK's biggest killers. A large proportion of these deaths occur as a result of post-MI cardiac remodelling eventually leading to heart failure. Recent genome-wide association studies elucidated a potential link between the PMCA1 gene, atp2b1, and these diseases. PMCA1 has been associated with many of the key features of heart failure and I found that PMCA1 expression is significantly increased 1 week post-MI in mouse models. This study therefore aimed to investigate the potential role of PMCA1 in the post-MI remodelling process using a transgenic mouse model expressing a heterozygous deletion of PMCA1 (PMCA1Ht). Following assessment of the anatomy of the coronary artery tree, MI via permanent ligation of the left anterior descending coronary artery, alongside a sham procedure was induced in either wild type or PMCA1Ht mice. Occurrence of ischaemia was confirmed by evaluation of plasma levels of cardiac troponin I (cTnI), conscious electrocardiography (ECG) and histologically. To assess whether heterozygous mutation of PMCA1 had an impact in the sub-acute and the chronic phase of the post-MI remodelling process, the animals were kept for either 1 or 4 weeks post-surgery, respectively. Unconscious ECG, echocardiography and cardiac haemodynamics were performed in vivo to assess cardiac function. To further characterise the cardiac response, histological and molecular analysis were performed at both time points. LAD coronary artery ligation led to ST-segment elevation, a significant increase in the plasma levels of cardiac troponin I 24 hours post-surgery and development of a transmural infarct in both wild type and PMCA1Ht-MI mice. Chronically post-MI, no major differences in the cardiac remodelling response appeared to be mediated by the heterozygous mutation of PMCA1. Sub-acutely post-MI, interestingly, whilst both wild type and PMCA1Ht-MI mice showed a significant deterioration in cardiac function, there were differences seen in cardiac structure suggesting wild type-MI mice experienced exacerbated pathological remodelling characterised by development of eccentric hypertrophy. For example, the wild type-MI hearts had significantly bigger endocardial circumferences, left ventricular (LV) lumens and LV mass to body weight ratios when compared to their PMCA1Ht counterparts. Unconscious ECG revealed a lower proportion of PMCA1Ht-MI mice experienced arrhythmic events when compared to wild types. In addition, a significant difference in infarct size was observed when wild type-MI hearts were compared to their PMCA1Ht counterparts 1 week post-surgery. This was accompanied by an increased expression of Bax, Bad and p53 in the wild type-MI mice and a significantly higher proportion of apoptotic cells in the wild type-MI hearts when compared to PMCA1Ht-MI hearts. Heterozygous mutation of PMCA1 might serve a protective role in the heart sub-acutely post-MI through modulation of apoptosis. In view of the findings presented here, pharmacological inhibition of PMCA1 early post-MI appears to be a promising treatment strategy that may prevent initial pathological cardiac remodelling and thereby postpone progression towards heart failure in the phase of cardiac de-compensation after MI.
Supervisor: Cartwright, Elizabeth ; Oceandy, Delvac Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available