[Truncated abstract] Our understanding of the actions of oestrogen on the vasculature has recently been questioned following the results of large clinical trials revealing a negative effect of hormone replacement therapy (HRT) on cardiovascular disease (CVD) risk amongst postmenopausal women. It is important to determine how a hormone with numerous positive effects on intermediate pathways of atherosclerosis fails to offer cardioprotection. Further investigation into the actions of oestrogen in the vasculature may add to our current understanding of the pathogenesis of atherosclerosis and oestrogen biology. The primary aim of this thesis was to investigate involvement of the oestrogen receptors (ERs) in atherosclerotic CVD and to provide further insight into the actions of oestrogen on the vasculature by studying the actions of oestrogen on the regulation of an oestrogen-responsive gene within human vascular cells. Following confirmation of ERa and ERß expression at the RNA and protein level in human aorta sections, correlations of receptor expression with age and atherosclerosis were examined. Significantly strong negative relationships of ERa, androgen receptor (AR), and progesterone receptor (PR) with age in both males and females were detected. No trend was detected between ERß expression and age. These findings suggest that the receptor-mediated actions of hormones in the vasculature may change with age. Further, this thesis compared for the first time sex hormone receptor expression in normal and adjacent atherosclerotic aortic tissue providing a critical assessment of receptor differences due to atherosclerosis. Results revealed reductions of all hormone receptors in early atherosclerotic versus normal aorta tissue. ... These results suggest that the 3'-UTR SNPS may have more of an influence on carotid thickening when oestrogen levels are lower, suggesting the importance of both genetic variation of the ERß gene and oestrogen status on carotid thickening. Finally, this was the first study to investigate oestrogen-induced regulation of angiotensinogen (AGT), a candidate gene for CVD, in human vascular cells. Oestrogen influenced AGT transcription in a cell specific manner. The overall influence of oestrogen on AGT transcription in the vasculature is unknown. This thesis adds to the knowledge of oestrogen and atherosclerosis by suggesting the involvement of the sex hormone receptors (ERa, ERß, PR and AR) in atherosclerosis, presenting ERß as a potentially important candidate gene for atherosclerosis, revealing interactions between estrogen status and associations of ERß SNPs with carotid thickening, and demonstrating vascular cell-specific actions of oestrogen on the regulation of a candidate gene for CVD. These factors may have contributed to the lack of cardio-protection following HRT, as revealed by large clinical trials.
| Identifer | oai:union.ndltd.org:ADTP/246433 |
| Date | January 2009 |
| Creators | Dennis, Maxine Elizabeth |
| Publisher | University of Western Australia. School of Pathology and Laboratory Medicine |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Maxine Elizabeth Dennis, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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