Date of Award

1-1-2010

Document Type

Campus Access Dissertation

Department

Pharmacology, Physiology and Neuroscience

Sub-Department

Biomedical Science

First Advisor

Gregory L. Brower

Abstract

Estrogen has been documented to attenuate tumor necrosis factor α (TNF-α) mediated proinflammatory effects on the cardiovascular system. The first half of this study sought to determine whether gender difference exists in cardiomyocyte remodeling during chronic volume overload (CVO) induced by aortocaval (AV) fistula. To this end, isolated cardiomyocyte dimension, sarcomere length, number of nuclei were measured in male and female rats after creation of an AV fistula. In sharp contrast to the progressive increases in cardiomyocyte length in female hearts at 7 days post-fistula and beyond, cardiomyocyte length in males did not increase significantly during the first 35 days. Another notable occurrence only in male hearts was a significant decrease in cardiomyocyte length at 5 days post-fistula, together with a reduced number of sarcomeres per cell with consistent sarcomere length, and 12% increase in the number of mononucleated cardiomyocytes. Interestingly, microtubule stabilizer, paclitaxel prevented the decrease of myocyte length and increase of mononucleated myocyte number. Together with images of BrdU labeling and mitotic spindle, these data suggest that gender difference exists in cardiomyocyte remodeling. Hyperplasia may play a role in male hearts but not female hearts during cardiac remodeling induced by CVO.

The second half of this study was designed to test the hypothesis that an adverse modulation of the cardiomyocyte basement membrane attachments in response to TNF-α is associated with the gender differences observed in cardiomyocyte remodeling. Clear gender differences in cardiomyocyte adhesion to laminin in sham and AV-fistula operated rats were found in that attachment of myocytes from male and ovariectomized female hearts was significantly reduced, while adhesion in the intact female sham and fistula groups was similar. Adhesion of myocytes treated with TNF-α was decreased 42% in intact females, but not in ovariectomized females. This reduction in myocyte adhesion by TNF-α was reversed by the Src kinase inhibitor, PP2. These results indicate that the TNF-α reduced cardiomyocyte adhesion involves Src kinases. Taken together, we conclude that TNF-α modulates myocyte adhesion and possibly accounts for the gender difference in myocyte adhesion and remodeling in the AV fistula model of heart failure.

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