Investigating the role of PDE4D7 in vascular smooth muscle cell migration
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Authors
Wudwud, Alexandra
Date
2015-08-31
Type
thesis
Language
eng
Keyword
phosphodiesterase , PDE4D7 , smooth muscle cell migration , RhoA ROCK
Alternative Title
Abstract
Inhibiting the maladaptive migration of vascular smooth muscle cells (VSMCs) in injured blood vessels can help to reduce the development of intimal lesions in vascular diseases such as atherosclerosis and restenosis. Cyclic adenosine monophosphate (cAMP) is involved in the regulation of VSMC migration and can be targeted in these diseases to reduce their impact. cAMP signaling is ubiquitous and dynamic, and requires control through signaling termination mechanisms. Phosphodiesterase (PDE) enzymes catalyze the hydrolysis of cAMP and are critical in the control of cAMP signaling. The spatial restriction of these enzymes in cells allows for the generation of distinct cAMP-mediated responses. The PDE4D gene family plays a dominant role in cAMP hydrolysis in migratory human VSMCs. Considerable interest exists in the idea that the unique N-terminal domains of PDE4D isoforms promote their spatial restriction in cells through selective interactions with other proteins, and that this localization allows individual isoforms to regulate discrete cellular functions. This study extends on previous work that examined the targeting of individual PDE4D isoforms in human arterial SMCs (HASMCs) through the overexpression of GFP constructs containing the unique N-terminal domains of the PDE4D isoforms (NT-PDE4D/GFP). The overexpression of NT-PDE4D7/GFP was observed to affect the morphology of migrating cells. In this study, using these N-terminal constructs and an RNAi-based strategy, we establish that PDE4D7 is involved in controlling rear retraction in migrating HASMCs. We show that altering PDE4D7 targeting and expression in these cells affects rear retraction largely through its ability to impact RhoA-ROCK signaling. We also report that PDE4D7 interacts with AKAP5, PKA and EPAC in HASMCs. Our results suggest a functional role for localized PDE4D7 activity in regulating cAMP-mediated rear retraction in migrating HASMCs, and identify PDE4D7 as a potential therapeutic target in controlling VSMC migration.
Description
Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2015-08-31 15:48:09.949
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Queen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canada
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This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.