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Regulation of NO synthesis by the urea cycle enzymes

尿素循环酶对 NO 合成的调节

基本信息

批准号：
10557020
负责人：
MORI Masataka
金额：
$ 8.32万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Nitric oxide (NO) is a messenger molecule functioning in vascular regulation, immunity, neurotransmission and others, and has been implicated in many diseases. NO is synthesized from arginine by NO synthase (NOS), and the availability of arginine has been shown to be one of the rate-limiting factors in NO production. Citrulline formed as a by-product of the NOS reaction can be recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL). We found that AS and AL are coinduced with inducible NOS (iNOS) in macrophages of rat and mouse tissues after LPS administration. Coinduction of iNOS and AS was also seen in immunostimulated rat glioma C6 cells and rat neuronal PC12 cells. In these cells, NO was synthesized from citrulline as well as from arginine, indicating operation of the citrulline-NO cycle. Coinduction of endothelial NOS (eNOS), AS and AL was found in aorta of streptozotocine-induced diabetic rats. eNOS was also found to be induced in astrocytes by l … More ow concentrations of LPS, and expression of the citrulline-NO cycle is to be tested. Cationic amino acid transporter (CAT)-2 was induced in macrophages, but not in C6 and PC12 cells. On the other hand, arginase may downregulate NO production by depleting arginine. We found that iNOS and arginase isoforms (type I and II) are coinduced by LPS in rodent tissues and cultured macrophages. In contrast, arginase was not induced in C6 and PC12 cells. When mouse macrophage-like RAW 264.7 cells were treated with LPS and interferon-γ, iNOS was induced, NO was produced and apoptosis followed. When iNOS and arginase II were coinduced, NO production was decreased and apoptosis was prevented. Furthermore, the cells transfected with an arginse I or II expression plasmid were rescued from apoptosis. These results indicate that NO production is regulated by uptake, recycling and degradation of arginine, and suggest that these enzymes can be good targets to regulate NO production in diseases in which oveproduction or impaired production of NO is implicated. Less

一氧化氮（NO）是一种信使分子，在血管调节、免疫、神经传递等方面起作用，并与许多疾病有关。NO由精氨酸通过NO合成酶（NOS）合成，精氨酸的可用性已被证明是NO产生的限速因素之一。作为NOS反应的副产物形成的瓜氨酸可以通过氨基琥珀酸合成酶（AS）和氨基琥珀酸裂解酶（AL）再循环为精氨酸。我们发现，在LPS刺激后，大鼠和小鼠组织巨噬细胞中的诱导型NOS（iNOS）共同诱导AS和AL。在免疫刺激的大鼠胶质瘤C6细胞和大鼠神经元PC 12细胞中也观察到iNOS和AS的共诱导。在这些细胞中，NO由瓜氨酸和精氨酸合成，表明瓜氨酸-NO循环的运作。糖尿病大鼠主动脉内皮型一氧化氮合酶（eNOS）、AS和AL共表达。eNOS在星形胶质细胞中也被发现诱导， ...更多信息低浓度的LPS和瓜氨酸-NO循环的表达。阳离子氨基酸转运体（CAT）-2在巨噬细胞中被诱导，而在C6和PC 12细胞中不被诱导。另一方面，精氨酸酶可以通过消耗精氨酸来下调NO的产生。我们发现，诱导型一氧化氮合酶和过氧化物酶亚型（I型和II型）的共同诱导的LPS在啮齿动物组织和培养的巨噬细胞。相反，在C6和PC 12细胞中，没有诱导的α-淀粉酶。LPS和IFN-γ处理小鼠巨噬细胞样RAW264.7细胞后，诱导iNOS产生，产生NO，并发生凋亡。当诱导型一氧化氮合酶和辅酶II共同诱导，NO的产生减少，细胞凋亡被阻止。此外，用β-半乳糖苷酶I或II表达质粒转染的细胞免于凋亡。这些结果表明，NO的产生是由精氨酸的摄取，再循环和降解调节，并表明这些酶可以是很好的目标，以调节NO的产生在疾病中，其中NO的产生减少或受损的生产是牵连。少