Retinoic acid inhibits nitric oxide synthase-2 expression through the retinoic acid receptor-alpha.
Retinoids are multipotent modulators of cellular functions and suppress cytokine-induced production of nitric oxide (NO) in several cell types. We have explored the mechanisms by which retinoic acid (RA) regulates NO production in rat aortic smooth muscle cells (VSMC), which express NOS2 in response to proinflammatory cytokines. RA inhibited interleukin-1beta (IL-1beta)-induced NOS2 mRNA expression and NO production. These effects were attenuated by the retinoic acid receptor (RAR) antagonist CD3106, indicating that they were mediated through retinoic acid receptors (RARs). The synthetic retinoid agonists CD336 (which specifically binds RARalpha) and CD367 (which binds all RARs) but not agonists specific for RARbeta, RARgamma, or RXRs reduced IL-1beta-induced NOS2 expression and NO production. When transfecting VSMC with a 1570-bp NOS2 promoter fragment fused to a luciferase reporter gene, the NOS2 promoter activity was inhibited by RA. These results indicate that retinoids modulate NO production in VSMC via RARalpha, which inhibits the transcription of the NOS2 gene.
Sirsjö
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A
Center for Molecular Medicine, Karolinska Institute at the Karolinska Hospital, Stockholm, S-171 76, Sweden. Allan.Sirsjo@cmm.ki.se
Gidlöf
A C
AC
Olsson
A
A
Törmä
H
H
Ares
M
M
Kleinert
H
H
Förstermann
U
U
Hansson
G K
GK
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
D007375:Interleukin-1; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat