Research for the clarification of the modulating mechanisms of pulmonary vascular remodeling associated with pulmonary hypertension

阐明肺动脉高压相关肺血管重构调节机制的研究

基本信息

批准号：
15591090
负责人：
DOI Shozaburo
金额：
$ 2.18万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Endothelium-derived nitric oxide (NO) plays a critical role in pulmonary vascular remodeling associated with pulmonary hypertension. The results and interpretations in the present research using pulmonary hypertensive model were described below. 1, L-arginine (L-arg), a substrate of NO, concentration in pulmonary arterial endothelial cells (PAECs) was decreased because of the accelerated activity of arginase, a first enzyme of urea cycle. 2, Endogenous NO synthase (NOS) inhibitors, N^G-monomethyl-L-arginine (L-NMMA) and N^G, N^G-dimethyl-L-arginine (ADMA), concentration in PAECs was increased because of the attenuated activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme related to catabolism of NOS inhibitors. 3, Ornithine decarboxylase (ODC), an enzyme acting on ornithine, activity was increased, probably followed by the increased putrescine, a powerful mitogen of pulmonary vascular smooth muscle cells. 4, Endothelial NOS activity as well as its protein expression wer … More e increased. 5, Accelerated arginase activity was recovered by N^G-hydroxy L-arginine (NOHA), an intermediate metabolite synthesized from L-arg by NOS. Based on these results, we concluded that lack of arginase activity inhibition by NOHA, followed by potentiated L-arg consumption, can lead to decrease NO production as so-called vicious circle in PAECs. In the present study, we couldn't perform to examine another signal transduction pathway in the downstream of arginase. Proline is synthesized by ornithine aminotransferase (OAT) from ornithine, and a mitogen of collagen fibers mainly existed in the vascular adventitia. As the future direction of the present study, taking into the presence of vicious circle among NOS and arginase signal transduction pathways, we are focusing on the NOS inhibitors, which are associated with NO production at the upper stream and can be metabolically regulated by DDAH. Moreover, we consider the development of DDAH agonist, which is available under the clinical settings, and hope that the agonist will be used for the radical treatment of PH. Less

内皮源性一氧化氮 (NO) 在与肺动脉高压相关的肺血管重塑中发挥着关键作用。本研究使用肺动脉高压模型的结果和解释如下所述 1、L-精氨酸 (L-arg)，一种底物。由于精氨酸酶（尿素循环 2 的第一个酶，内源性 NO 合酶）活性加速，肺动脉内皮细胞 (PAEC) 中的 NO 浓度降低。 (NOS) 抑制剂，N^G-单甲基-L-精氨酸 (L-NMMA) 和 N^G，N^G-二甲基-L-精氨酸 (ADMA)，由于二甲基精氨酸二甲氨基水解酶的活性减弱，PAEC 中的浓度增加(DDAH)，一种与 NOS 抑制剂分解代谢相关的酶 3，鸟氨酸脱羧酶 (ODC)，一种作用于 NOS 的酶。鸟氨酸的活性增加，可能随之而来的是腐胺的增加，腐胺是肺血管平滑肌细胞的一种强大的有丝分裂原。 4，内皮 NOS 活性及其蛋白质表达增加 5，N^ 恢复了加速的精氨酸酶活性。 G-羟基 L-精氨酸 (NOHA) 是 NOS 从 L-arg 合成的中间代谢产物。根据这些结果，我们得出结论，缺乏精氨酸酶活性抑制。 NOHA，随后增强的 L-arg 消耗，可导致 PAEC 中 NO 的产生减少，即所谓的恶性循环。在本研究中，我们无法检查精氨酸酶合成下游的另一个信号转导途径。鸟氨酸转氨酶（OAT）和胶原纤维丝裂原主要存在于血管外膜中，作为本研究的未来方向，考虑到NOS和之间存在恶性循环。精氨酸酶信号转导途径，我们重点关注NOS抑制剂，它与上游NO的产生相关，并且可以通过DDAH进行代谢调节。此外，我们考虑开发可在临床环境下使用的DDAH激动剂，以及希望激动剂能够用于PH的根治治疗。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Involvement of accumulated endogenous NOS inhibitors and accelerated arginase activity in impairing the NO production in pulmonary arterial hypertension of the rat.

累积的内源性 NOS 抑制剂和加速的精氨酸酶活性参与损害肺动脉高压大鼠的 NO 产生。

DOI：
发表时间：
2005
期刊：
American Journal of Respiratory and Critical Care Medicine Vol 2
影响因子：
0
作者：
Sasaki A;Doi S;Wakimoto H;Takahashi R;Azuma H.
通讯作者：
Azuma H.

Involvement of accumulated endogenous NOS inhibitors and accelerated arginase activity in impairing the NO production in pulmonary arterial hypertension of the rat

积累的内源性 NOS 抑制剂和加速的精氨酸酶活性损害大鼠肺动脉高压中 NO 的产生

DOI：
发表时间：
2005
期刊：
American Thoracic Society 2005 San Diego International Conference Abstracts Issue Volume 2
影响因子：
0
作者：
Sasaki A;Doi S;Wakimoto H;Takahashi R;Azuma H
通讯作者：
Azuma H