Institutional Repository of Peking University School of Basic Medical Sciences
|Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage|
|Yan, Junhao1,2; Manaenko, Anatol2; Chen, Sheng2,4; Klebe, Damon2; Ma, Qingyi2; Caner, Basak2; Fujii, Mutsumi2; Zhou, Changman1; Zhang, John H.2,3|
|关键词||Microvascular Permeability Protease Activated Receptor-1 Rat Subarachnoid Hemorrhage Ve-cadherin|
|WOS标题词||Science & Technology|
|类目[WOS]||Clinical Neurology ; Peripheral Vascular Disease|
|研究领域[WOS]||Neurosciences & Neurology ; Cardiovascular System & Cardiology|
|关键词[WOS]||THROMBIN RECEPTOR ; MOLECULAR-BASIS ; CEREBRAL EDEMA ; BLEEDING-TIME ; BRAIN ; PERMEABILITY ; ADHESION ; HEMOSTASIS ; ANTAGONIST ; JUNCTIONS|
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 beta-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. (Stroke. 2013;44:1410-1417.)
|作者单位||1.Loma Linda Univ, Dept Physiol & Pharmacol, Med Ctr, Loma Linda, CA 92354 USA|
2.Loma Linda Univ, Dept Anesthesiol, Med Ctr, Loma Linda, CA 92354 USA
3.Zhejiang Univ, Sch Med, Dept Neurosurg, Affiliated Hosp 2, Hangzhou 310003, Zhejiang, Peoples R China
4.Peking Univ, Dept Anat & Histol, Sch Basic Med Sci, Beijing 100871, Peoples R China
|Yan, Junhao,Manaenko, Anatol,Chen, Sheng,et al. Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage[J]. STROKE,2013,44(5):1410-+.|
|APA||Yan, Junhao.,Manaenko, Anatol.,Chen, Sheng.,Klebe, Damon.,Ma, Qingyi.,...&Zhang, John H..(2013).Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage.STROKE,44(5),1410-+.|
|MLA||Yan, Junhao,et al."Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage".STROKE 44.5(2013):1410-+.|