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Document Type

Dissertation - University Access Only

Award Date

2014

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Zhuqie Jin

Abstract

To investigate whether or not tight junctions is involved in myocardial ischemia/reperfusion injury (I/R), we utilized ex vivo mice ischemia/reperfusion model. Since ischemic preconditioning (IPC) is one of the most effective procedures known to protect hearts against I/R injury, it was considered as positive control. We found that under electron microscope, there were clear TJs between coronary endothelial cells of mouse hearts. I/R caused the collapse of TJs whereas IPC sustained the structure of TJs. I/R increased extravascular EBA content in the heart but decreased the expression of tight junction protein ZO-2 in the cytoskeleton. IPC reduced cardiac EBA content and enhanced the translocation of ZO-2 from cytosol to cytoskeleton. Infiltration of T cells in myocardial tissue has been observed in patients with coronary heart disease and this could partly due to increased tight junction permeability. PKC θ is vital for activation of T lymphocytes. In the second part of this project, two approaches were used to deactivate mature T cell: pharmacological inhibition with a selective PKC θ inhibitor (PI) and genetic manipulation with Rag 1 knockout (KO) mice. Pretreatment with PI protected hearts against I/R injury as evidenced by low CK release and decreased infarct size in C57BL/6J hearts. PI reduced the translocation of PKC θ. Myocardial I/R injury was attenuated in Rag 1 KO mice, denoted by small portion of infarct size and low CK release. PI induced cardioprotection was abrogated in Rag1 KO mice.Similarly, T cell infiltration and impairment of tight junction between endothelial cells were also observed in hearts of diabetic patients. In this study, streptozotocin (STZ) induced type 1 diabetic cardiomyopathy model was used. Our results indicated that PI had no effects on high blood glucose level in both WT mice and Rag1 KO mice. STZ induced cardiac fibrosis in WT mice but not in Rag1 KO mice. Remarkably, cardiac fibrosis was attenuated in PI group. PI also improved cardiac contractility in diabetic mice. PI decreased pT538-PKC-θ expression, reduced the infiltration of T cells and increased tight junction protein ZO-1 expression within the WT diabetic hearts.

Library of Congress Subject Headings

Protein kinase C
Tight junctions (Cell biology)
Coronary heart disease
Myocardial reperfusion

Description

Includes bibliographical references (pages 81-104)

Format

application/pdf

Number of Pages

117

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

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