Ca^<2+> sensitization and deficiency of myosin light chain dephosphorylation in the pathogenesis of cerebral vasospasm

脑血管痉挛发病机制中Ca^<2>敏化和肌球蛋白轻链去磷酸化缺陷

基本信息

批准号：
11307023
负责人：
SASAKI Tomio
金额：
$ 18.92万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11307023/
关键词：
subarachnoid hemorrhage cerebral vasospasm vasocontraction Ca^<2+> sensitization experimental vasospasm cerebral vasospasm vascular smooth muscle rho kinase myosin light chain kinase myosin binding subunit phosphorylation calcium sen

项目摘要

The pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) has been intensively investigated but is not still fully understood. Cerebral vasospasm is associated with changes in the activity of several intracellular signal transduction pathways including the activation of small GTPase Rho A and Rho-kinase. Activation of Rho-kinase by Rho A causes phosphorylation of the myosin-binding subunit of myosin phosphatase complex, which leads to the inactivation of myosin phosphatase. Thus, the stimulation of small G-protein signaling results in the continuous contraction of cerebral arteries without changes in [Ca^<2+>]i, which may be responsible for the pathophysiology of cerebral vasospasm. However, the systemic assessment of relationship Ca^<2+> sensitization and cerebral vasospasm has been lacked previously. First we recorded simultaneously isometric tension and intracellular Ca^<2+> concentration in basilar artery from dogs, and several agonists contract cerebral vessels through Ca^<2+> sensitization mechanism and Rho/Rho kinase pathway. Second, we recorded simultaneously isometric tension and intracellular Ca^<2+> concentration in basilar artery from experimental SAH model dogs. The tendency of increasing Ca^<2+> sensitization in spastic basilar arteries was observed. On the other hand, we attended a bioactive molecule, sphingosine-1-phosphate (S1P) that can be released from platelets and stimulates Rho/Rho-kinase system. We investigated whether or not S1P is considered as a novel spasmogenic substance involved in the cerebral vasospasm after SAH.

蛛网膜下腔出血（SAH）后脑血管痉挛的发病机制已得到深入研究，但仍不完全清楚。脑血管痉挛与多种细胞内信号转导途径活性的变化有关，包括小 GTP 酶 Rho A 和 Rho 激酶的激活。 Rho A 激活 Rho 激酶会导致肌球蛋白磷酸酶复合物的肌球蛋白结合亚基磷酸化，从而导致肌球蛋白磷酸酶失活。因此，小G蛋白信号传导的刺激导致脑动脉持续收缩而[Ca^2+]i不发生变化，这可能是脑血管痉挛的病理生理学原因。然而，以前缺乏对Ca ^ 2+ 致敏与脑血管痉挛关系的系统评估。首先我们同时记录了狗基底动脉的等长张力和细胞内Ca^2+浓度，并且几种激动剂通过Ca^2+敏化机制和Rho/Rho激酶途径收缩脑血管。其次，我们同时记录了实验SAH模型狗的基底动脉的等长张力和细胞内Ca 2+ 浓度。观察到痉挛的基底动脉中Ca 2+ 敏化增加的趋势。另一方面，我们研究了一种生物活性分子，1-磷酸鞘氨醇 (S1P)，它可以从血小板中释放并刺激 Rho/Rho 激酶系统。我们研究了S1P是否被认为是一种与SAH后脑血管痉挛有关的新型致痉物质。