Arginase modulates nitric oxide production in activated macrophages
Arginase modulates nitric oxide production in activated macrophages
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DOI：
10.1152/ajpheart.1998.274.1.h342
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发表时间：
1998-01-01
影响因子：
4.8
通讯作者：
Kuo, L
中科院分区：
文献类型：
--
作者：
Chang, CI;Liao, JC;Kuo, L
在巨噬细胞和许多其他细胞类型中，一氧化氮合酶 (NOS) 和精氨酸酶使用 L-精氨酸作为底物，分别产生一氧化氮 (NO) 和尿素。由于 L-精氨酸的可用性是活化巨噬细胞中 NO 合成的主要决定因素，因此我们假设精氨酸酶可能通过耗尽该细胞类型中的共同底物来减少 NO 产生。为了检验这一假设，我们研究了精氨酸酶抑制剂 L-正缬氨酸对脂多糖（LPS，1.0 μg/ml）激活 J774A.1 小鼠巨噬细胞 22 小时 NO 产生的影响。在缺乏 LPS 的情况下，巨噬细胞产生低水平的 NO。相反，在 LPS 存在的情况下，这些细胞产生的 NO 显着增加。增加细胞外 L-精氨酸水平 (0.01-0.8 mM) 会导致活化巨噬细胞的 NO 产量随之增加。 L-正缬氨酸 (10 mM) 可特异性抑制精氨酸酶活性（即，尿素产量减少 50%），而不改变 NOS 活性，增强活化巨噬细胞的 NO 产量（减少 55%）。 L-正缬氨酸对NO产生的增强与细胞外L-精氨酸的水平呈负相关。在细胞外 L-精氨酸水平较低时观察到 NO 产生更明显的增加，即 0.05 和 0.1 mM 细胞外 L-精氨酸分别增加 55% 和 28%。当L-精氨酸浓度超过0.5 mM时，L-正缬氨酸作用消失。这些结果表明精氨酸酶可以与 NOS 竞争其共同底物，从而抑制 NO 的产生。当细胞外 L-精氨酸的供应有限时，这种调节机制可能特别重要。
In macrophages and many other cell types, L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively. Because the availability of L-arginine is a major determinant for NO synthesis in the activated macrophage, we hypothesized that NO production may be reduced by arginase via depleting the common substrate in this cell type. To test this hypothesis, we investigated the effect of an arginase inhibitor, L-norvaline, on NO production in J774A.1 mouse macrophages activated by lipopolysaccharide (LPS, 1.0 mu g/ml) for 22 h. In the absence of LPS, macrophages produced a low level of NO. In contrast, NO production from these cells was significantly increased in the presence of LPS. Increasing extracellular levels of L-arginine (0.01-0.8 mM) produced a concomitant increase in NO production of activated macrophages. L-Norvaline (10 mM), which specifically inhibits arginase activity (i.e., reducing urea production by 50%) without altering NOS activity, enhanced NO production (by 55%) from activated macrophages. The enhancement of NO production by L-norvaline was inversely related to the extracellular level of L-arginine. A more pronounced increase in NO production was observed at the lower level of extracellular L-arginine, i.e., a 55 vs. 28% increase for 0.05 and 0.1 mM extracellular L-arginine, respectively. When the L-arginine concentration exceeded 0.5 mM, the L-norvaline effect was abolished. These results indicate that arginase can compete with NOS for their common substrate and thus inhibit NO production. This regulatory mechanism may be particularly important when the extracellular supply of L-arginine is limited.