Zuraidah Abdullah
Suppression of PKC-α attenuates TNF-α-evoked cerebral barrier breakdown via regulations of MMP-2 and plasminogen–plasmin system
Abdullah, Zuraidah; Bayraktutan, Ulvi
Abstract
Ischaemic stroke, accompanied by neuroinflammation, impairs blood-brain barrier integrity through a complex mechanism involving both protein kinase C (PKC) and urokinase. Using an in vitro model of human blood-brain barrier (BBB) composed of brain microvascular endothelial cells (HBMEC) and astrocytes, this study assessed the putative roles of these elements in BBB damage evoked by enhanced availability of pro-inflammatory cytokine, TNF-α. Treatment of HBMEC with TNF-α significantly increased the mRNA and protein expressions of all plasminogen-plasmin system (PPS) components, namely tissue plasminogen activator, urokinase, urokinase plasminogen activator receptor and plasminogen activator inhibitor-1 and also the activities of urokinase, total PKC and extracellular MMP-2. Inhibition of urokinase by amiloride abated the effects of TNF-α on BBB integrity and MMP-2 activity without affecting that of total PKC. Conversely, pharmacological inhibition of conventional PKC isoforms dramatically suppressed TNF-α-induced overactivation of urokinase. Knockdown of PKC-α gene via specific siRNA in HBMEC suppressed the stimulatory effects of TNF-α on protein expression of all PPS components, MMP-2 activity, DNA fragmentation rates and pro-apoptotic caspase-3/7 activities. Establishment of co-cultures with BMEC transfected with PKC-α siRNA attenuated the disruptive effects of TNF- on BBB integrity and function. This was partly due to elevations observed in expression of a tight junction protein, claudin-5 and partly to prevention of stress fibre formation. In conclusion, specific inhibition of PKC-α in cerebral conditions associated with exaggerated release of pro-inflammatory cytokines, notably TNF- may be of considerable therapeutic value and help maintain endothelial cell viability, appropriate cytoskeletal structure and basement membrane.
Citation
Abdullah, Z., & Bayraktutan, U. (2016). Suppression of PKC-α attenuates TNF-α-evoked cerebral barrier breakdown via regulations of MMP-2 and plasminogen–plasmin system. BBA - Molecular Basis of Disease, 1862(7), 1354-1366. https://doi.org/10.1016/j.bbadis.2016.03.014
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 30, 2016 |
Online Publication Date | Apr 17, 2016 |
Publication Date | 2016-07 |
Deposit Date | Oct 26, 2016 |
Publicly Available Date | Oct 26, 2016 |
Journal | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |
Print ISSN | 0925-4439 |
Electronic ISSN | 0006-3002 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 1862 |
Issue | 7 |
Pages | 1354-1366 |
DOI | https://doi.org/10.1016/j.bbadis.2016.03.014 |
Keywords | TNF-α; blood-brain barrier; PKC-α; PPS components; MMP-2; claudin-5; apoptosis; stress fibres |
Public URL | https://nottingham-repository.worktribe.com/output/798190 |
Publisher URL | http://www.sciencedirect.com/science/article/pii/S0925443916300710 |
Additional Information | This article is maintained by: Elsevier; Article Title: Suppression of PKC-α attenuates TNF-α-evoked cerebral barrier breakdown via regulations of MMP-2 and plasminogen–plasmin system; Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bbadis.2016.03.014; Content Type: article; Copyright: © 2016 Elsevier B.V. |
Contract Date | Oct 26, 2016 |
Files
Suppression of PKC-α attenuates TNF-α-evoked x.pdf
(1.5 Mb)
PDF
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0
You might also like
The Role of Stem Cells as Therapeutics for Ischaemic Stroke
(2024)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: discovery-access-systems@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search