DOI
https://doi.org/10.25772/C9H1-WE71
Defense Date
2011
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Integrative Life Sciences
First Advisor
Paul Fawcett
Abstract
Pulmonary arterial hypertension (PAH) is a disease of the lung vessels that causes severe effects on the right ventricle of the heart; ultimately, most patients with severe PAH die as a result of right heart failure. However, little is known about the causes of right heart failure. Here, we describe a pattern of gene expression that differs between the normal rat left ventricle (LV) and right ventricle (RV). These genes are known to be involved in the development of the heart as well as adaptations to the heart during stress. This gene expression pattern is used as a baseline to describe changes in gene expression the occur in the RV as a result of adaptive hypertrophy, stimulated by chronic hypoxia, or right ventricular failure (RVF), caused by administration of Su5416 and hypoxia. The genes differing between RVF and hypertrophy encode glycolytic enzymes, mitochondrial electron transport chain complexes, cell-growth promoting proteins, and angiogenic capillary maintenance proteins. Additionally, we show that RVF is associated with an increase in the serum cytokine production of IL-1 beta, IL-10, TNF-alpha, and VEGF. Finally, we show that treatment with the beta-adrenergic receptor blocker carvedilol partially changed the gene expression pattern seen with RVF. The most profound effects were on the genes encoding glycolytic enzymes and mitochondrial electron transport chain complexes. Together, these results show that the normal LV and RV have a distinct pattern of expression and that the failing RV is characterized by changes in cell growth, angiogenesis, and energy utilization. Treatment with carvedilol can partially reverse these gene expression changes in the failing RV.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
September 2011