The role of platelet-derived spasmogens and Rho/Rho-kinase pathway in the pathogenesis of cerebral vasospasm.

血小板源性痉挛原和 Rho/Rho 激酶通路在脑血管痉挛发病机制中的作用。

基本信息

批准号：
14207053
负责人：
SASAKI Tomio
金额：
$ 17.06万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207053/
关键词：
subarachnoid hemorrhage cerebral vasospasm Rho Rho-kinase pathway sohingosine-1-phosphate thrombin thrombin receptor Ca2+ sensitization oxidative stress クモ膜下出血ミオシン軽鎖 subarachnoid hemorrhage cerebral vasospasm Rho kinase myosin

项目摘要

Cerebral vasospasm is one of the major critical determinants of the prognosis alter subarachnoid hemorrhage (SAH). As shown in our previous discovery that sphingosine-1-phosphate activates the Rho/Rho-kinase pathway in cerebral vasospasm, the activation and up-regulation of Rho and Rhokinase have been suggested to play an important role in the pathogenesis of cerebral vasospasm,In the present study, we investigated the roles of thrombin, one of the other potent spasmogens, and the roles of Rho/Rho-kinase pathway in cerebral vasospasm. First, we investigated the effect of thrombin and its receptor expression in the hypercontractil response of spastic basilar artery of a rabbit SAH model. Thrombin up-regulated the expression of thrombin receptor and induced a hypercontractile response to thrombin itself in the spastic artery. The impaired desensitization of thrombin receptor also contributed to the hyperoontractiliy of the spastic artery. Second, we investigated the role of Rhokinase in Ca^<2+> sensitization in bovine middle cerebral artery. Thromboxane A_2 analogue, one of the patent spasmogens, induced the sustained contraction with enhanced Ca^<2+> sensitivity of the artery, which was achieved both in myosin fight chain phosphorylation-dependent and -independent manners. Third, we discovered that oxidative stress induced the contractile response of cerebral artery to bradykinin, a physiological vasorelaxant, through the activation of Rho/Rho-kinase pathway and endothelial dysfunction, which thus suggested a loss of endothelium-dependent relaxation under an oxidative stress alter SAH.Our basic researches showed the importance of Rho/Rho-kinase pathway activation in the molecular mechanisms underlying pathogenesis of cerebral vasospasm. In particular, the regulation of thrombin receptor in the upstream of Rho/Rho-kinase pathways was indicated to be a novel therapeutic target for the prophylactic managemert of cerebral vasospasm.

脑血管痉挛是蛛网膜下腔出血（SAH）预后的主要决定因素之一。正如我们之前发现的1-磷酸鞘氨醇在脑血管痉挛中激活Rho/Rho激酶通路所示，Rho和Rho激酶的激活和上调被认为在脑血管痉挛的发病机制中发挥着重要作用。在本研究中，我们研究了凝血酶（另一种有效的痉挛原之一）的作用，以及 Rho/Rho 激酶通路在脑中的作用血管痉挛。首先，我们研究了凝血酶及其受体表达对兔蛛网膜下腔出血模型痉挛基底动脉过度收缩反应的影响。凝血酶上调凝血酶受体的表达，并诱导痉挛动脉中凝血酶本身的过度收缩反应。凝血酶受体脱敏受损也导致痉挛动脉过度收缩。其次，我们研究了Rhokinase在牛大脑中动脉Ca^2+敏化中的作用。血栓素A_2类似物，一种专利的痉挛原，诱导持续收缩并增强动脉的Ca 2+ 敏感性，这通过肌球蛋白战斗链磷酸化依赖性和非依赖性方式实现。第三，我们发现氧化应激通过激活Rho/Rho激酶途径和内皮功能障碍，诱导脑动脉对缓激肽（一种生理性血管舒张剂）的收缩反应，这表明氧化应激改变下内皮依赖性舒张功能的丧失。 SAH。我们的基础研究表明Rho/Rho激酶通路激活在脑血管痉挛发病分子机制中的重要性。特别是，Rho/Rho激酶途径上游凝血酶受体的调节被认为是预防性治疗脑血管痉挛的新治疗靶点。