Date of Award
2014
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Biomolecular Sciences
First Advisor
David B. Murray
Second Advisor
Rodney C. Baker
Third Advisor
Tracy A. Brooks
Relational Format
dissertation/thesis
Abstract
Chronic hypertension has long been known to cause left ventricular remodeling. Although previous studies pointed towards inflammation as the pathological driver of cardiac remodeling, the exact mechanistic pathway associated with pressure overload-induced cardiac remodeling remains to be elucidated. In order to address this issue, we designed this study to determine pathways associated with pressure overload induced cardiac remodeling and identify therapeutic targets to attenuate this maladaptive cardiac remodeling. Rats with surgically constricted abdominal aorta were used as an animal model for pressure overload and associated Left ventricular (LV) structure and functional changes were measured by pressure-volume admittance catheterization. Human cardiac fibroblasts were used to assess the specific mechanistic pathways associated with prostaglandin D2 (PGD2) mediated fibrotic response. At the 14 day period, pressure overloaded animals shosignificant changes in LV structural and functional parameters. Cyclooxygenase-2 (COX-2) inhibition with Nimesulide significantly attenuated the structural and functional changes associated with LV remodeling due to pressure overload. Prevention treatment with Nimesulide shothat the beneficial effects seen with acute treatment were still prevalent even after discontinuation of treatment. Intervention treatment with Nimesulide shothat only a few parameters like chamber size and stroke volume can be revered by COX-2 inhibition in rats with already established LV remodeling. Similar results were observed with prevention treatment with HQL-79 a specific H-Prostaglandin D synthase inhibitor, indicating that the PGD2 is a major driver for LV remodeling downstream of COX-2. Intervention treatment with HQL-79 showed, selective blockade of H- PGD synthase can significantly reverse maladaptive changes in cardiac structure and function indicated by LV mass index, chamber size, stroke volume and total collagen levels. In vitro studies on human cardiac fibroblasts have shown that both prostaglandin D receptors the DP2 and DP2 receptors down-regulate COX-2 expression. DP1 receptor was shown to up-regulate both Collagen 1A and 3A mRNA expressions, whereas DP2 receptor activation led to elevation of Collagen 1A and reduction in collagen 3A mRNA expression. These results indicate that COX-2 and downstream PGD2 are major drivers for pressure overload induced cardiac remodeling. H-PGD synthase was found to be a potential therapeutic target to prevent and reverse left ventricular remodeling induced by pressure overload.
Recommended Citation
Nagalla, Krishna T., "The Efficacy Of Prostaglandin Synthase Inhibition On Attenuating Pressure Overload Induced Cardiac Remodeling" (2014). Electronic Theses and Dissertations. 724.
https://egrove.olemiss.edu/etd/724