Abstract | BACKGROUND: METHODS: Cerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-κB activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways. RESULTS: Cerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-κB-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-κB-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca2+-dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion. CONCLUSIONS: tPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium.
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Authors | Volodymyr Gerzanich, Min Seong Kwon, Seung Kyoon Woo, Alexander Ivanov, J Marc Simard |
Journal | PloS one
(PLoS One)
Vol. 13
Issue 4
Pg. e0195526
( 2018)
ISSN: 1932-6203 [Electronic] United States |
PMID | 29617457
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Fibrinolytic Agents
- NF-kappa B
- Sulfonylurea Receptors
- TRPM Cation Channels
- Tissue Plasminogen Activator
- Matrix Metalloproteinase 9
- Calcium
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Topics |
- Animals
- Brain
(blood supply, drug effects, metabolism, pathology)
- Brain Ischemia
(drug therapy, metabolism, pathology)
- Calcium
(metabolism)
- Cell Line
- Endothelial Cells
(drug effects, metabolism)
- Fibrinolytic Agents
(pharmacology)
- Humans
- Male
- Matrix Metalloproteinase 9
(metabolism)
- Mice
- Microvessels
(drug effects, metabolism, pathology)
- NF-kappa B
(metabolism)
- Rats, Wistar
- Sulfonylurea Receptors
(metabolism)
- TRPM Cation Channels
(metabolism)
- Tissue Plasminogen Activator
(pharmacology)
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