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    Investigation of the cardiac endothelin system post myocardial infarction in the rat

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    SherryLA_2001redux.pdf (37.21Mb)
    Date
    2001
    Author
    Sherry, Lorcan Adrian
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    Abstract
     
     
    Survivors of acute myocardial infarction (MI) have a high risk of developing chronic heart failure (CHF). In human CHF there is evidence that plasma levels of the potent vasoconstrictor peptide, endothelin (ET)-l and its precursor big ET-1 are increased, correlate positively with disease severity, and may be important predictors of outcome. The aims of this thesis were to investigate the heart as a source of ET-1 synthesis and to investigate the role of the cardiac ET-1 system during scar formation in the early stage post-MI and also during progression of CHF in a rat model. MI in the rat was induced by surgical ligation of the left anterior descending coronary artery. The myocardial ET system was investigated using immunohistochemical and in situ hybridisation techniques.
     
    In the normal heart, immunoreactive ET-1 was identified in the vascular endothelium and myoendothelial cells in the myocardium. Staining for ET-1 was intense and uniform in cardiomyocytes throughout the myocardium. In situ hybridisation confirmed that sites of preproET-1 mRNA expression coincided with sites of immunoreactive ET-1. These results indicate that the myocardium has the capacity to endogenously produce ET-1 in both myoendothelial cells and cardiomyocytes.
     
    Investigation of ET-1 immunoreactivity during scar formation 2, 7 and 14 days postMI indicated an early transient increase in ET-1 in the infarct, which peaks at 7 days. At this time point, ET-1 could be localised to proliferating fibroblasts, infiltrating inflammatory cells and in the endothelia of newly forming vessels, suggesting a role for ET-1 in scar formation early post-MI.
     
    Though increased ET-1 staining could be localised at a cellular level in the developing infarct, further studies were needed to identify whether ET-1 was beneficial or detrimental during scar formation. Therefore, the effect on early stage scar formation of an ETa/b receptor antagonist (A-182086) fed to rats immediately after coronary artery ligation surgery and for the duration (2, 7 or 14 days) of the study was investigated. In rats treated with antagonist, viable myocardial content of the infarcted region was significantly greater at both 7 and 14 days post-MI compared to untreated rats. The salvaged myocardium also demonstrated a vascular supply and ET-1 immunoreactivity similar to that observed in normal viable myocardium from sham-operated rats.
     
    In rat hearts 5 and 12 weeks post-MI, the area of infarction induced by coronary artery ligation had formed a fibrosed scar. ET-1 staining was located uniformly in all non-infarcted areas of the heart, but only in the few remaining viable myocytes in the infarcted region. PreproET-1 mRNA expression matched ET-1 immunohistochemical visualisation in all areas of the heart. ETa receptor expression was similar in the non-infarcted areas of post-MI rat hearts compared to that in areas from age-matched sham-operated rat hearts. However, ETb receptor expression and ETb immunoreactivity were increased in the non-infarcted areas of rat hearts at 12 weeks but not 5 weeks post MI and co-localised with an increase in the transcriptional growth factor ERK.
     
    These results suggest that the heart has the capacity to endogenously produce ET-1 and that changes in the ET-1 system occur at different stages post-MI. Furthermore, these changes may be detrimental to acute myocardial cell survival post-MI, and in the later stages post-MI during progressive remodelling of the non-infarcted myocardium.
     
    URI
    http://hdl.handle.net/1842/30750
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    • Biological Sciences thesis and dissertation collection

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