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Date of Award

2004

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Physiology and Pharmacology

First Advisor

Denis Meerdink

First Committee Member

Paul Williams

Second Committee Member

Roshanak Rahimian

Third Committee Member

Eric Thomas

Fourth Committee Member

David Thomas

Abstract

The angiogenic and cardioprotective effects of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) in the ischemic myocardium have been studied, but expression and release of endogenous FGF-2 and VEGF during myocardial ischemia are poorly understood. In addition, nitric oxide synthase isoforms eNOS and iNOS may play a role in myocardial ischemia. The purpose of this study was to investigate the release of FGF-2 and expression of FGF-2, VEGF, eNOS, and iNOS in the normal and ischemic heart. In Phase I, serum FGF-2 levels in patients undergoing treadmill stress test were measured to investigate correlation between serum FGF-2 levels and presence of ischemic heart disease. The study found that serum FGF-2 in ischemia-positive and ischemia-negative patients was not significantly elevated after treadmill stress test, and serum FGF-2 levels did not differ significantly between ischemia-positive and ischemia-negative patients. In Phase II, FGF-2 levels in coronary effluent from isolated perfused rabbit hearts subjected to low-flow ischemia was measured. Results suggest that FGF-2 is released into the coronary effluent of isolated perfused hearts over time and that this release may be elevated in ischemic (50% flow) hearts. Furthermore, the present study indicates that FGF-2 is released immediately after surgical isolation and instrumentation of the isolated heart. A linear model was developed to describe the release of FGF-2 from the isolated heart as a function of the coronary flow rate Q : [special characters omitted]where t = time and Q = 1 and 3.01 for normal and 50% flow rates respectively. In Phase III, effect of acute low-flow ischemia on FGF-2, VEGF, eNOS, and iNOS mRNA expression was measured in isolated perfused hearts using RT/PCR. Preliminary results indicate that FGF-2, VEGF, and iNOS mRNA expression is upregulated and eNOS expression is decreased in ischemic hearts suggesting that these growth factors play a role in short-term response of the myocardium to ischemia. The results of this study suggest that FGF-2, VEGF, and iNOS mRNA expression are increased, eNOS expression is decreased, and FGF-2 is released in response to low-flow ischemia in the isolated perfused heart.

Pages

105

ISBN

9780496903368 , 0496903365

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