Regulation of NO synthesis by the urea cycle enzymes

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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