Circadian Rhythms of Endothelial Nitric Oxide Synthase and Toll-like Receptors 2 Production in Females with Rheumatoid Arthritis Depending on NOS3 Gene Polymorphism

Author(s): Kateryna Zaichko, Nataliia Zaichko, Oleksandr Maievskyi, Oleksandr Korotkyi, Tetyana Falalyeyeva, Sharmila Fagoonee, Rinaldo Pellicano, Ludovico Abenavoli, Mykola Stanislavchuk*

Journal Name: Reviews on Recent Clinical Trials

Volume 15 , Issue 2 , 2020

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Abstract:

Background: Rheumatoid Arthritis (RA) is an autoimmune polygenic disease characterized by rapid disability progression and high prevalence. Progression of RA is closely associated with chronobiological changes in the production of some hormones and inflammatory mediators, influencing the disease course and therapy efficacy. The main pathogenetic mechanism of RA is angiogenesis, which is controlled by biological clock-genes. Further investigation of circadian rhythms of angiogenic mediators production in RA patients may be considered as important and relevant. The aim of this study was to establish daily variability of serum endothelial Nitric Oxide Synthase (NOS3) and toll-like receptors 2 (sTLR2) levels in female RA patients depending on the NOS3 gene polymorphism.

Methods: We examined 173 RA patients (100% female) aged 43.7 ± 7.35 years and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). RA was diagnosed by ACR/EULAR 2010 criteria. Blood serum NOS3 and sTLR2 levels were determined at 08:00 and 20:00 using Cloud-Clone Corp kits (USA). NOS3 T-786С (rs2070744) polymorphism was determined by Real-Time PCR (Bio-Rad iCycler IQ5) using SNP-express kits. The SPSS22 software package was used for statistical processing of the results.

Results: Females with RA demonstrated oppositely directed serum NOS3 and sTLR2 daily changes: NOS3 level in the morning (08:00) was lower than in the evening (+ 45.5 ± 30.7%), and sTLR2 level in the evening (at 20:00) was lower than in the morning (-21.6 ± 13.1%). RA patients had differences in NOS3 and sTLR2 production depending on NOS3 T786C genotype. CC subjects had NOS3 level at 08:00, 20:00 and day average levels lower (16-25%), and sTLR2 level higher (24-27%) than those of TT subjects. RA patients, carriers of CC genotype, had higher chances of NOS3 and sTLR2 aberrant production compared to TT and TC genotype carriers (OR = 2.99 and 4.79, respectively).

Conclusion: RA patients demonstrated oppositely directed circadian changes of serum NOS3 and sTLR2. CC genotype carriers had lower NOS3 and higher sTLR2 production rates than TT and TC genotype carriers.

Keywords: Chronobiological changes, circadian rhythms, endothelial nitric oxide synthase, polymorphism, rheumatoid arthritis, toll-like receptors 2.

[1]
Khimion LV, Yashchenko OB, Danyliuk SV. Management of patients with rheumatoid arthritis of General practitioner - family doctor. Fam Med 2016; 2(64): 6-15.
[2]
Neyko YeM, Yatsyshyn RI, Shtefiuk OV. Rheumatoid Arthritis is a modern view on the problem. Ukrainian Rheumatol J 2009; 2(36): 35-9.
[3]
Cutolo M. Glucocorticoids and chronotherapy in rheumatoid arthritis. RMD Open 2016; 2(1) e000203
[http://dx.doi.org/10.1136/rmdopen-2015-000203] [PMID: 27042335]
[4]
To H. Chronotherapy for rheumatoid arthritis: current perspectives. Chronophysiol Therap 2016; 6: 47-53.
[http://dx.doi.org/10.2147/CPT.S87421]
[5]
Jensen LD, Gyllenhaal C, Block K. Circadian angiogenesis. Biomol Concepts 2014; 5(3): 245-56.
[http://dx.doi.org/10.1515/bmc-2014-0009] [PMID: 25372756]
[6]
Nakagawa T, Sato W, Kosugi T, Johnson RJ. Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy. J Diabetes Res 2013; 2013 184539
[http://dx.doi.org/10.1155/2013/184539] [PMID: 24386643]
[7]
Saber T, Veale DJ, Balogh E, et al. Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis. PLoS One 2011; 6(8) e23540
[http://dx.doi.org/10.1371/journal.pone.0023540] [PMID: 21858161]
[8]
Cho K, Demissie S, Dupuis J, et al. Polymorphisms in the endothelial nitric oxide synthase gene and bone density/ultrasound and geometry in humans. Bone 2008; 42(1): 53-60.
[http://dx.doi.org/10.1016/j.bone.2007.09.051] [PMID: 17980690]
[9]
Wang L, Wu W, Chen J, Li Y, Xu M, Cai Y. MicroRNA microarray-based identification of involvement of mir-155 and mir-19a in development of oral lichen planus (olp) by modulating Th1/Th2 balance via targeting eNOS and toll-like receptor 2 (TLR2). Med Sci Monit 2018; 24: 3591-603.
[http://dx.doi.org/10.12659/MSM.907497] [PMID: 29813046]
[10]
McGarry T, Biniecka M, Gao W, et al. Resolution of TLR2-induced inflammation through manipulation of metabolic pathways in Rheumatoid Arthritis. Sci Rep 2017; 7(1): 43165.
[http://dx.doi.org/10.1038/srep43165] [PMID: 28225071]
[11]
Hossain MJ, Morandi E, Tanasescu R, et al. The soluble form of toll-like receptor 2 is elevated in serum of multiple sclerosis patients: A novel potential disease biomarker. Front Immunol 2018; 9: 457.
[http://dx.doi.org/10.3389/fimmu.2018.00457] [PMID: 29593720]
[12]
Houssen ME, El-Mahdy RH, Shahin DA. Serum soluble toll-like receptor 2: a novel biomarker for systemic lupus erythematosus disease activity and lupus-related cardiovascular dysfunction. Int J Rheum Dis 2016; 19(7): 685-92.
[http://dx.doi.org/10.1111/1756-185X.12452] [PMID: 25123610]
[13]
Bukach OP, Sydorchuk LP, Fediv OI. The effect of T-786C polymorphism of the gene endothelial nitric oxide synthase on cytokine profile in patients with rheumatoid arthritis. Clin and experim pathol 2017; 16(1/59): 39-43.
[14]
Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69(9): 1580-8.
[http://dx.doi.org/10.1136/ard.2010.138461] [PMID: 20699241]
[15]
Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 1992; 35(5): 498-502.
[http://dx.doi.org/10.1002/art.1780350502] [PMID: 1575785]
[16]
van Vollenhoven RF. Sex differences in rheumatoid arthritis: More than meets the eye.... BMC Med 2009; 7: 12.
[http://dx.doi.org/10.1186/1741-7015-7-12] [PMID: 19331649]
[17]
Yan L, Silver R. Neuroendocrine underpinnings of sex differences in circadian timing systems. J Steroid Biochem Mol Biol 2016; 160: 118-26.
[http://dx.doi.org/10.1016/j.jsbmb.2015.10.007] [PMID: 26472554]
[18]
Dosenko VE, Lutaĭ IaM, Zagoriĭ VIu, Parkhomenko AN, Moĭbenko AA. [Frequencies of allelic polymorphism of endothelial NO-synthase gene in patients with acute coronary syndrome in Ukrainian population]. Tsitol Genet 2005; 39(2): 49-54.
[PMID: 16161413]
[19]
Drozdovska SB. T-786→ C promoter gene polymorphism of eNOS (endothelial NO-synthase) in Ukrainian athletes. Ecological aspects of modern biology and medical genetics 2012; 6: 46-53.
[20]
Sydorchuk L, Bukach O, Fediv O, et al. Cytokines cascade changes in patients with rheumatoid arthritis depending on endothelial NO-synthase (T-786C) genes polymorphism. Balkan Medical Union 2017; 1(52): 32-8.
[21]
Melchers I, Blaschke S, Hecker M, Cattaruzza M. The -786C/T single-nucleotide polymorphism in the promoter of the gene for endothelial nitric oxide synthase: insensitivity to physiologic stimuli as a risk factor for rheumatoid arthritis. Arthritis Rheum 2006; 54(10): 3144-51.
[http://dx.doi.org/10.1002/art.22147] [PMID: 17009241]
[22]
Gonzalez-Gay MA, Llorca J, Palomino-Morales R, Gomez-Acebo I, Gonzalez-Juanatey C, Martin J. Influence of nitric oxide synthase gene polymorphisms on the risk of cardiovascular events in rheumatoid arthritis. Clin Exp Rheumatol 2009; 27(1): 116-9.
[PMID: 19327239]
[23]
Miyamoto Y, Saito Y, Nakayama M, et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T-->C mutation associated with coronary spastic angina. Hum Mol Genet 2000; 9(18): 2629-37.
[http://dx.doi.org/10.1093/hmg/9.18.2629] [PMID: 11063722]
[24]
Nakayama M, Yasue H, Yoshimura M, et al. T-786-->C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99(22): 2864-70.
[http://dx.doi.org/10.1161/01.CIR.99.22.2864] [PMID: 10359729]
[25]
Yu L, Guo Y, Gong Y, et al. Effects of bisoprolol on circadian rhythm of nitric oxide and endothelial nitric oxide synthase. Am J Hypertens 2013; 26(1): 149.
[http://dx.doi.org/10.1093/ajh/hps061]
[26]
Silver AC, Buckley SM, Hughes ME, Hastings AK, Nitabach MN, Fikrig E. Daily oscillations in expression and responsiveness of Toll-like receptors in splenic immune cells. Heliyon 2018; 4(3) e00579
[http://dx.doi.org/10.1016/j.heliyon.2018.e00579] [PMID: 29862343]
[27]
Speer T, Rohrer L, Blyszczuk P, et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 2013; 38(4): 754-68.
[http://dx.doi.org/10.1016/j.immuni.2013.02.009] [PMID: 23477738]


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VOLUME: 15
ISSUE: 2
Year: 2020
Page: [145 - 151]
Pages: 7
DOI: 10.2174/1574887115666200416143512
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