Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Gregory L Brower

Second Advisor

Joseph S Janicki

Abstract

Numerous studies have shown evidence of gender differences in heart failure. A hallmark of heart failure is the remodeling of the hearts' structures, particularly the ventricles. In males with aortocaval (AV) fistula chronic volume overload model of heart failure, ventricular hypertrophy and dilatation are compensatory responses to this increase in volume. The continued remodeling of the myocardium becomes maladaptive and ultimately leads to the development of heart failure. However in females with the chronic volume overload model of heart failure, the adverse remodeling response is attenuated, in which they are afforded a better degree of cardioprotection, which does not progress into failure. Interestingly, the ovarian hormone, estrogen has been shown to mediate this response; but how estrogen mediates this response in the myocardium has not been elucidated. The studies detailed herein were used to test the hypothesis that estrogen regulation of immune cells is cardioprotective. To accomplish this, male rats were supplemented with estrogen and subjected to the AV fistula. After 3 days post- fistula, genes expressed in the left ventricle were examined using a real time PCR array. A total of 55 inflammatory genes which were modified (> 2-fold change) at three days post-fistula was reduced to 20 genes by estrogen treatment, whereas 12 genes were comparably modulated in both fistula groups. In decreasing order, the greatest percentage of changes in gene expression in response to the imposition of the volume overload were among metabolism, receptor, membrane scaffolding and cell adhesion molecules, inflammatory/stress response, signal transduction, sympathetic nervous system, proteases and ion channels. Interestingly, estrogen treatment suppressed many of the genes that are responsible for adverse remodeling of the myocardium, suggesting estrogen may modulate the cardiac immune cells. The cardiac immune cells have been linked to adverse remodeling responses that occurs secondary to chronic volume overload. Therefore, to test if estrogen was modulating the cardiac immune cells; the cardiac immune cells of estrogen treated animals were then used in coincubation experiments with the cardiac fibroblast to assess the immune cells ability to modulate fibroblast regulation of the extracellular matrix (ECM). These studies demonstrate that estrogen can modulate the immune cells and immune cell secretory products to modify the adverse remodeling response in the cardiac fibroblast. Estrogen-treated immune cells were able to significantly upregulate collagen production by cardiac fibroblasts; meanwhile, significantly decreasing matrix metalloproteinase (MMPs) protein levels and activity in the adult cardiac fibroblasts. Lastly, mast cell secretory products were used to assess the diverse remodeling response in adult cardiac fibroblasts. These studies also demonstrate that different secretory products can have profound effects on the adult cardiac fibroblasts ability to maintain the ECM in the heart. The findings in these studies indicate that estrogen modulation of immune cells is cardioprotective by mediating fibroblast regulation of the ECM.

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