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Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage
- Source :
- Stroke. 44:1410-1417
- Publication Year :
- 2013
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2013.
-
Abstract
- Background and Purpose— Plasma thrombin concentration is increased after subarachnoid hemorrhage (SAH). However, the role of thrombin receptor (protease-activated receptor-1 [PAR-1]) in endothelial barrier disruption has not been studied. The aims of this study were to investigate the role of PAR-1 in orchestrating vascular permeability and to assess the potential therapeutics of a PAR-1 antagonist, SCH79797, through maintaining vascular integrity. Methods— SCH79797 was injected intraperitoneally into male Sprauge-Dawley rats undergoing SAH by endovascular perforation. Assessment was conducted at 24 hours after SAH for brain water content, Evans blue content, and neurobehavioral testing. To explore the role of PAR-1 activation and the specific mechanism of SCH79797’s effect after SAH, Western blot, immunoprecipitation, and immunofluorescence of hippocampus tissue were performed. A p21-activated kinase-1 (PAK1) inhibitor, IPA-3, was used to explore the underlying protective mechanism of SCH79797. Results— At 24 hours after SAH, animals treated with SCH79797 demonstrated a reduction in brain water content, Evans blue content, and neurobehavioral deficits. SCH79797 also attenuated PAR-1 expression and maintained the level of vascular endothelial-cadherin, an important component of adherens junctions. Downstream to PAR-1, c-Src–dependent activation of p21-activated kinase-1 led to an increased serine/threonine phosphorylation of vascular endothelial-cadherin; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial-cadherin with endocytosis orchestrator β-arrestin-2. These pathological states were suppressed after SCH79797 treatment. Conclusions— PAR-1 activation after SAH increases microvascular permeability, at least, partly through a PAR-1-c-Src-p21-activated kinase-1-vascular endothelial-cadherin phosphorylation pathway. Through suppressing PAR-1 activity, SCH79797 plays a protective role in maintaining microvascular integrity after SAH.
- Subjects :
- Male
Pathology
medicine.medical_specialty
Subarachnoid hemorrhage
Perforation (oil well)
Vascular permeability
Naphthols
Blood–brain barrier
Article
Permeability
Rats, Sprague-Dawley
chemistry.chemical_compound
Thrombin
Western blot
Thrombin receptor
medicine
Animals
Pyrroles
Receptor, PAR-1
Disulfides
Enzyme Inhibitors
Evans Blue
Advanced and Specialized Nursing
medicine.diagnostic_test
business.industry
Brain
Subarachnoid Hemorrhage
medicine.disease
Rats
medicine.anatomical_structure
p21-Activated Kinases
chemistry
Blood-Brain Barrier
Quinazolines
Neurology (clinical)
Cardiology and Cardiovascular Medicine
business
medicine.drug
Subjects
Details
- ISSN :
- 15244628 and 00392499
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Stroke
- Accession number :
- edsair.doi.dedup.....29aced0922fb7f06080fb02f4a5ea751
- Full Text :
- https://doi.org/10.1161/strokeaha.113.678474