权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigation of mechanotransduction mechanism in pulmonary artery for therapeutic application of experimental pulmonary hypertension.

肺动脉力传导机制研究在实验性肺动脉高压治疗中的应用。

基本信息

批准号：
14572059
负责人：
TANABE Yoshiyuki
金额：
$ 2.24万
依托单位：
University of Shizuoka
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

项目摘要

Pathogenicity of vasculature with chronically increased hemodynamics such as hypertension and arteriosclerosis may be attributable in part to biological responses of cardiovascular tissues against mechanical stimuli. The research purpose of this study is to find a new therapeutic target for experimental pulmonary hypertension through pharmacological regulation of mechanotransduction mechanisms of pulmonary artery.Mechanical stretching to 180% of initial muscle length produces the excessive arterial tension, which is considered to be similar degree in the pulmonary hypertension. The stretching of the pulmonary artery activates downstream signal of integrin, a putative mechanosensor; nevertheless, the stretching augments productions of prostanoids in an integrin-dependent (TXA_2 and PGF_<2α>) and independent (untransformed (ut-)PGH_2, PGE_2, and PGI_2) manner. Of these prostanoids, moreover, the ut-PGH_2 was primarily responsible for the stretch-induced contraction of the pulmonary arter … More y. Assuming that integrin-independent pathway of PG-production might be mediated by secretory phospholipase A_2 (sPLA_2), the effects of indoxam, a highly selective inhibitor for sPLA_2, on the contraction of pulmonary artery and the production of ut-PGH_2 in response to stretching were examined. In a normal rabbit pulmonary artery, indoxam preferentially inhibit the stretch-induced contraction (IC_<50>=0.513 μM), which was about 20-fold more effective than acetylcholine-induced contraction (IC_<50>=10.25 μM). Production of ut-PGH_2 was abolished by indoxam at this time. In the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PH rats), a significant increase in the steady-state mRNA level for group X sPLA_2 was observed. Indoxam (1-3 μM) completely abolished rhythmic contraction as well as concomitant production of ut-PGH_2 during the prolonged stretching, which is an aberrant character of the pulmonary artery of MCT-PH rats.These results suggest that sPLA_2-mediated production of ut-PGH_2 causes stretch-induced contraction and/or increasing vascular tone of the pulmonary arteries in both normal and the pulmonary hypertension. Successful blockade by Indoxam of ut-PGH_2-production and contractile responses of the pulmonary arteries in both normal and diseased status suggest that sPLA_2 would become a new therapeutic target for experimental pulmonary hypertension. Less

慢性血流动力学增加的脉管系统（如高血压和动脉硬化）的致病性可能部分归因于心血管组织对机械刺激的生物反应。本研究的目的是通过药物调节肺动脉的机械传导机制，寻找实验性肺动脉高压的治疗新靶点，机械牵张至初始肌长的180%，产生与肺动脉高压程度相似的过度动脉张力。肺动脉的牵张激活了整合素下游信号，整合素是一种假定的机械感受器，然而牵张以整合素依赖性（TXA_2和PGF_<2 α>）和非依赖性（未转化的（ut-）PGH_2、PGE_2和PGI_2）的方式增加前列腺素类的产生。在这些前列腺素中，ut-PGH_2是牵张性肺动脉收缩的主要原因 ...更多信息 y.假定PG产生的非整合素依赖性途径可能是由分泌型磷脂酶A_2（sPLA_2）介导的，本实验观察了高度选择性sPLA_2抑制剂indoxam对牵张引起的肺动脉收缩和ut-PGH_2产生的影响。在正常兔肺动脉，吲哚辛优先抑制牵张性收缩（IC_= 0.513 μ M），比乙酰胆碱（IC_= 10.25 μ M）强20倍。<50><50>此时indoxam消除了ut-PGH_2的产生。在野百合碱诱导的肺动脉高压大鼠（MCT PH大鼠）肺动脉中，观察到X组sPLA_2的稳态mRNA水平显著增加。Indoxam（1 - 3 μ M）可完全抑制MCT-PH大鼠肺动脉在牵张过程中的节律性收缩和ut-PGH_2的产生，提示sPLA_2介导的ut-PGH_2的产生可引起正常和肺动脉高压大鼠肺动脉牵张收缩和/或血管张力增加。Indoxam成功地阻断了正常和病变状态下ut-PGH_2的产生和肺动脉的收缩反应，提示sPLA_2可能成为实验性肺动脉高压治疗的新靶点。少