Bernal, Paula Jimena
(2010)
PULMONARY ENDOTHELIUM AND THE ROLE OF ZINC IN HYPOXIA INDUCED VASOCONSTRICTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Hypoxic pulmonary vasoconstriction (HPV) is a unique physiological response of the lung that acts to optimize gas exchange by diverting blood flow from poorly ventilated regions. The endothelium has been thought to play a mostly modulatory role in this phenomenon through the synthesis of vasoactive agents such as nitric oxide (NO), prostacyclin, and endothelin. Data is provided showing that acute hypoxia induces increases in NO biosynthesis, promoting S-nitrosation of the metal binding protein metallothionein (MT), which resulted in intracellular release of zinc. Hypoxia released zinc induced contraction of pulmonary endothelial cells and contributed to vasoconstriction of small, non-muscularized intra-acinar arteries in isolated perfused mouse lungs (IPL). The relevance of this NO/MT/Zn pathway in HPV was illustrated by pharmacological inhibition of NO synthesis and analysis of the response in MT knockout (MT-/-) mice, both of which resulted in a blunted pressure response to hypoxia in IPL. Signaling pathways were delineated, indicating how changes in intracellular zinc can alter the actin cytoskeleton and promote cellular contraction. It was found that either hypoxia or exogenous zinc resulted in increases in the formation and alignment of actin stress fibers. These changes were mediated through the inhibition of myosin light chain phosphatase (MLCP), which promoted phosphorylation of myosin light chain (MLC) and tension generation. Activation of PKC appeared to play a role in this process, as indicated by activation and translocation of the enzyme in response to both hypoxia and/or increases in labile zinc, and by the blunted contractile response in isolated endothelial cells following pharmacological inhibition of PKC or utilization of a PCKε dominant negative construct. These data suggest that the NO released in response to hypoxia promotes increases in MLC phosphorylation through zinc-dependent pathways, which in turn are responsible for the force induction and cell stability necessary to elicit an active contractile response in pulmonary endothelium.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
19 August 2010 |
| Date Type: |
Completion |
| Defense Date: |
12 August 2010 |
| Approval Date: |
19 August 2010 |
| Submission Date: |
17 August 2010 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cell Biology and Molecular Physiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
contraction; endothelium; hypoxia; Hypoxic pulmonary vasoconstriction; metallothionein; zinc |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08172010-192901/, etd-08172010-192901 |
| Date Deposited: |
10 Nov 2011 20:00 |
| Last Modified: |
15 Nov 2016 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9158 |
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