Chronic Hypoxia Modulates the Interleukin-1β–Stimulated Inducible Nitric Oxide Synthase Pathway in Cardiac Myocytes

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Abstract
Background We wished to determine whether the cytokine-inducible nitric oxide synthase (iNOS) pathway is modulated by chronic hypoxia in vitro. Methods and Results We investigated the effects of the proinflammatory cytokine interleukin (IL)-1β on expression of iNOS mRNA, iNOS protein, and NO production in cultured neonatal rat cardiomyocytes subjected to 1% O 2 for 48 hours. Among several cytokines tested, IL-1β was the most effective in stimulating NO production, which was maximum at 48 hours. In parallel, IL-1β 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-1β–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-κB induced by IL-1β were decreased, which may account at least in part for the decrease in iNOS expression. Conclusions These data indicate that IL-1β 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.

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