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

Cross-interactions between CO and NO signaling in microvascular endothelium

微血管内皮中 CO 和 NO 信号传导之间的交叉相互作用

基本信息

批准号：
17500261
负责人：
KAJIMURA Mayumi
金额：
$ 1.73万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17500261/
关键词：
heme oxygenase carbon monoxide nitric oxide cerebral circulation nitric oxide synthase pial circulation nitnic oxide pial microcirculation NO imaging diaminofluorescein

项目摘要

Carbon monoxide (CO) is synthesized endogenously by heme oxygenase (HO) which degrades heme to biliverdin-IXα. Like nitric oxide (NO), CO has a vasodilatory property in the liver where endogenous NO production appears low. However, in the brain producing relatively high NO, how these gaseous monoxides interact each other to control cerebrovascular tone is unknown. Here we show that CO derived from HO acts as a tonic regulator against NO-dependent vasodilatation in the adult rat brain. We found that suppressing endogenous CO caused an increase in arteriolar diameter that was accompanied by an increase in local NO generation. We examined further if such an inhibitory function of CO on NO generation is mediated through the ability of CO to bind the prosthetic heme of gas-producing enzymes. Using cultured porcine aortic endothelial cells (PAECs), we measured NO generation by an NO-specific fluorescent dye. Treatment with CO-releasing molecule attenuated the time-dependent elevation of NO generation. This effect of CO to suppress NO generation was cancelled by exposing PAECs to white light raising a possibility that CO directly targets The ferrous heme of NOS3 to inhibit the catalytic activity. Furthermore, immunohistochemical analyses of the rat brain showed that HO-2 occurred in neurons and arachnoid trabecullar cells where NOS1 resided, and also in vascular endothelium expressing NOS3, suggesting colocalization of CO-and NO-generating sites. Our results demonstrate an importance of spatial relationship among the gas-producing enzymes and their reception systems in evaluating roles of the two gases.

一氧化碳(CO)是由血红素加氧酶(HO)降解血红素生成胆绿素-IXα内源合成的。与一氧化氮(NO)一样，CO在肝脏具有血管扩张特性，内源性NO产量似乎较低。然而，在大脑中产生相对较高的NO，这些气体一氧化碳是如何相互作用来控制脑血管张力的尚不清楚。在这里，我们展示了来自HO的CO在成年大鼠大脑中起到了紧张性调节作用，对抗NO依赖的血管扩张。我们发现抑制内源性CO导致小动脉直径增加，并伴随着局部NO生成的增加。我们进一步研究了CO对NO生成的这种抑制作用是否通过CO与产气酶的假体血红素结合的能力来介导。利用培养的猪主动脉内皮细胞(PAECs)，我们测量了一种NO特异性荧光染料产生的NO。CO释放分子的处理减弱了NO生成量随时间的增加。CO抑制NO生成的这种作用通过将PAECs暴露在白光下而被抵消，增加了CO直接靶向NOS3的亚铁血红素以抑制催化活性的可能性。此外，免疫组织化学分析显示，HO-2存在于NOS1所在的神经元和蛛网膜小梁细胞中，也存在于表达NOS3的血管内皮细胞中，这表明一氧化碳和一氧化氮的产生部位共存。我们的结果证明了产气酶和它们的接收系统之间的空间关系在评估这两种气体的作用方面的重要性。