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Circadian fluctuations of endothelial nitric oxide synthase activity in females with rheumatoid arthritis: a pilot study

  • Observational Research
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Abstract

Rheumatoid arthritis (RA) is a disease associated with circadian disorders of steroid hormones or cytokine secretion which induce inflammatory, destructive and proliferative processes in the synovial joints. Angiogenesis plays an important role in RA, but circadian rhythms of the angiogenic mediator production, especially endothelial nitric oxide synthase (NOS3), are still unclear. NOS3 takes part in regulation of endothelial functions, inflammation, and bone remodeling process. Studying circadian rhythms of NOS3 production in RA patients will make an improvement in understanding the angiogenic—inflammatory pathways relevant to rheumatic diseases. The aim of the study was to test the hypothesis of a diurnal variation in circulating levels of NOS3 in RA patients. A cross-sectional monocentric pilot study of circadian variability of endothelial nitric oxide synthase in a Ukrainian population was conducted between March and July 2017. We examined 36 RA patients (100% women) and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). Blood samples were collected four times per day (at 08:00; 14:00; 20:00 and 02:00) for two consecutive days. Serum NOS3 concentration was measured by ELISA (Cloud-Clone Corp kit). The study was conducted in compliance with bioethical standards. The SPSS22 software package was used for statistical processing of the results. A diurnal variation in circulating levels of NOS3 in healthy women was established, with peak values appearing in the evening and acrophase at 20:00, and low values in the morning, with batiphase at 08:00. In patients with RA serum, NOS3 levels were substantially decreased throughout the day compared to the control. In RA patients, a diurnal variation in circulating levels of NOS3 was also established. However, the variability of NOS3 production was higher in RA patients than in the control group. For example, in RA patients the difference between morning/evening values of NOS3 was 1.3 times higher (p < 0.05) than in the control. Negative correlations were found between the morning NOS3 levels and RA activity markers such as DAS28 and the number of tender and swollen joints. The diurnal variation in circulating levels of NOS3 in women with RA as well as in healthy women was found. However, in RA patients, a decrease in NOS3 production was observed, especially in the morning, which was associated with an increase in the disease activity. Thus, the circadian rhythm of circulating NOS3 can be opposite to the circadian rhythm of secretion of main inflammatory regulators in RA.

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Acknowledgements

External language editing support was provided by a translation agency ‘Visa’.

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Authors and Affiliations

  1. Department of Internal Medicine No.1, National Pirogov Memorial Medical University, Vinnytsya, Ukraine

    Kateryna Zaichko & Mykola Stanislavchuk

  2. Department of Chemistry and Biochemistry, National Pirogov Memorial Medical University, Vinnytsya, Ukraine

    Nataliia Zaichko

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  1. Kateryna Zaichko
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  2. Mykola Stanislavchuk
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  3. Nataliia Zaichko
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All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work, and took full responsibility for the integrity of the study. KZ wrote the initial version of the manuscript, collected and interpreted the data and edited the manuscript. MS and NZ supervised the research, took part in interpretation of the data and wrote the manuscript.

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Correspondence to Kateryna Zaichko.

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Zaichko, K., Stanislavchuk, M. & Zaichko, N. Circadian fluctuations of endothelial nitric oxide synthase activity in females with rheumatoid arthritis: a pilot study. Rheumatol Int 40, 549–554 (2020). https://doi.org/10.1007/s00296-020-04525-4

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  • DOI: https://doi.org/10.1007/s00296-020-04525-4

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