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Genotype-dependent NOS-3 expression and rheumatoid arthritis

The -786C-variant of the endothelial nitric oxide synthase nos-3 gene has been shown to be associated with coronary artery disease because of a blunted inducibility of gene expression [1]. IL-10, a cytokine involved in TH1/TH2-cell differentiation, is a new stimulus for NOS-3 expression [2].

We here address the question whether IL-10-induced NOS-3 expression is decreased in individuals with the -786C/C genotype and, if so, whether a TH1-mediated disease like rheumatoid arthritis is associated with this genotype.

Endothelial cells were isolated from an umbilical cord vein of known genotype and cultured as described [1]. The expression of NOS-3 was analysed by real-time semi-quantitative RT-PCR [1]. Genotyping was performed as described elsewhere [1]. Patients met the revised criteria of the ACR for the classification of rheumatoid arthritis, and donated blood samples after informed consent.

Primary human umbilical vein endothelial cells with the -786C/C genotype did not respond with an increase in NOS-3 expression to IL-10 incubation (5 ng/ml). This defect could be repaired after pre-incubation of the cells with a decoy oligonucleotide (10 μmol/l) directed against the C-variant of the promoter. Among 587 patients with rheumatoid arthritis tested, incidences for the -786C/C genotype were significantly higher than in the general population (17% versus 11.7%; P < 0.01).

NOS-3 is one mediator of anti-inflammatory IL-10 actions. Individuals with the -786C/C nos-3-genotype have an increased risk for the development of rheumatoid arthritis. This might be due to the IL-10 insensitivity of the C-variant of the promoter.

References

  1. Cattaruzza M, Guzik TJ, Slodowsky W, Pelvan A, Becker J, Halle M, Buchwald AB, Channon KM, Hecker M: Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease. Circ Res. 2004, 95: 841-847. 10.1161/01.RES.0000145359.47708.2f.

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Acknowledgement

Supported by a grant of the BMBF (competence network rheumatism) to IM.

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Cattaruzza, M., Melchers, I. & Hecker, M. Genotype-dependent NOS-3 expression and rheumatoid arthritis. Arthritis Res Ther 7, P104 (2005). https://doi.org/10.1186/ar1625

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  • DOI: https://doi.org/10.1186/ar1625

Keywords

  • Rheumatoid Arthritis
  • Nitric Oxide
  • Coronary Artery Disease
  • Umbilical Cord
  • Human Umbilical Vein Endothelial Cell