Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Leslie A. Leinwand

Second Advisor

Zhe Chen

Third Advisor

Russell L. Moore

Fourth Advisor

Timothy A. McKinsey

Fifth Advisor

Robin D. Dowell

Abstract

Significant sexual dimorphisms have been demonstrated in the development, presentation and outcome of cardiovascular disease (CVD) in humans as well as in animal models. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. Additionally, even though CVD is the number one killer of women in the U.S., women have traditionally been omitted from clinical trials and female animals have commonly been excluded from basic research studies. This research bias has led to the development of cardiovascular therapeutics that are not as effective in women relative to men suffering from the same disease. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively treat all patients with CVD. In this thesis I characterize the baseline differences in function, gene expression and estrogen signaling that exist in the contractile cells of the heart, the cardiac myocytes. Specifically, I characterized the expression, localization and signaling characteristics of the estrogen receptor, ERα, in neonatal and adult cardiac myocytes. Because I did not observe sexual dimorphisms in the expression or localization of ERα in adult cardiac myocytes, I sought to investigate other potential mechanisms mediating the sexually dimorphic functional differences I observed in the whole heart, cardiac myocytes and myofibrils. I therefore conducted an RNA-sequencing experiment to identify cardiac myocyte gene expression differences between the sexes. In addition to demonstrating that hundreds of genes are differentially expressed between male and female myocytes, I also identified sexually dimorphic enriched pathways, such as the PKA pathway, that could be mediating the differences in contractility observed at baseline. Overall these studies provide insight to the sex differences in cardiac function, gene expression and signaling pathways that exist during baseline conditions, which is essential for better understanding the disparity in cardiovascular disease development between the sexes.

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