Kacimi R, Long C S, Karliner J S
Veterans Affairs Medical Center, the Cardiovascular Research Institute, and the Department of Medicine, University of California, San Francisco 94121, USA.
Circulation. 1997 Sep 16;96(6):1937-43. doi: 10.1161/01.cir.96.6.1937.
We wished to determine whether the cytokine-inducible nitric oxide synthase (iNOS) pathway is modulated by chronic hypoxia in vitro.
We investigated the effects of the proinflammatory cytokine interleukin (IL)-1beta on expression of iNOS mRNA, iNOS protein, and NO production in cultured neonatal rat cardiomyocytes subjected to 1% O2 for 48 hours. Among several cytokines tested, IL-1beta was the most effective in stimulating NO production, which was maximum at 48 hours. In parallel, IL-1beta induced expression of both iNOS mRNA and protein. Hypoxia alone had no effect on NO production, iNOS gene expression, or protein induction. However, chronic hypoxia decreased IL-1beta-stimulated NO production, mRNA expression, and protein level in cardiac myocytes. Radioligand binding and electrophoretic mobility shift assays showed that during chronic hypoxia, IL-1 receptor density and activity of the transcription factor NF-kappaB induced by IL-1beta were decreased, which may account at least in part for the decrease in iNOS expression.
These data indicate that IL-1beta induces iNOS gene expression, de novo synthesis of iNOS protein, and NO generation in neonatal rat cardiomyocytes and that chronic hypoxia appears to be a potent negative regulator of iNOS expression in these cells.
我们希望确定细胞因子诱导型一氧化氮合酶（iNOS）途径在体外是否受慢性低氧调节。
我们研究了促炎细胞因子白细胞介素（IL）-1β对在1%氧气条件下培养48小时的新生大鼠心肌细胞中iNOS mRNA、iNOS蛋白表达及一氧化氮（NO）生成的影响。在测试的几种细胞因子中，IL-1β在刺激NO生成方面最为有效，在48小时时达到最大值。同时，IL-1β诱导iNOS mRNA和蛋白的表达。单独低氧对NO生成、iNOS基因表达或蛋白诱导无影响。然而，慢性低氧降低了心肌细胞中IL-1β刺激的NO生成、mRNA表达和蛋白水平。放射性配体结合和电泳迁移率变动分析表明，在慢性低氧期间，IL-1受体密度以及IL-1β诱导的转录因子NF-κB的活性降低，这可能至少部分解释了iNOS表达的降低。
这些数据表明，IL-1β诱导新生大鼠心肌细胞中iNOS基因表达、iNOS蛋白的从头合成以及NO生成，并且慢性低氧似乎是这些细胞中iNOS表达的有效负调节因子。
