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学科主题: 基础医学
题名:
Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage
作者: 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
刊名: STROKE
发表日期: 2013-05-01
DOI: 10.1161/STROKEAHA.113.678474
卷: 44, 期:5, 页:1410-+
收录类别: SCI
文章类型: Article
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
英文摘要:

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.)

语种: 英语
所属项目编号: NS053407
项目资助者: National Institutes of Health/National Institute of Neurological Disorders and Stroke
WOS记录号: WOS:000318030000049
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/50617
Appears in Collections:基础医学院_期刊论文

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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

Recommended Citation:
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-+.
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