Retinoic acid inhibits nitric oxide synthase-2 expression through the retinoic acid receptor-alpha

Retinoids are multipotent modulators of cellular functions and suppress cyt okine-induced production of nitric oxide (NO) in several cell types. We hav e explored the mechanisms by which retinoic acid (RA) regulates NO producti on in rat aortic smooth muscle cells (VSMC), which express NOS2 in response to proinflammatory cytokines. RA inhibited interleukin-1 beta (IL-1 beta)- induced NOS2 mRNA expression and NO production. These effects were attenuat ed by the retinoic acid receptor (RAR) antagonist CD3106, indicating that t hey were mediated through retinoic acid receptors (RARs). The synthetic ret inoid agonists CD336 (which specifically binds RAR alpha) and CD367 (which binds all RARs) but not agonists specific for RAR beta, RAR gamma, or RXRs reduced IL-1 beta-induced NOS2 expression and NO production. When transfect ing VSMC with a 1570-bp NOS2 promoter fragment fused to a luciferase report er gene, the NOS2 promoter activity was inhibited by Rk These results indic ate that retinoids modulate NO production in VSMC via RAR alpha, which inhi bits the transcription of the NOS2 gene. (C) 2000 Academic Press.