Skip to main content
SpringerLink
Log in

Evaluation of salivary and serum methylated arginine metabolites and nitric oxide synthase in advanced periodontitis patients

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

Methylated arginine metabolites and nitric oxide synthase (NOS) play a critical role in regulating endothelial function. The aim of this study was to determine levels of NOS, and methylated arginine metabolites (ADMA, SDMA, homoarginine, arginine, and L-NMMA) and IL-6 in serum and saliva in patients with advanced periodontal diseases and identify their association with clinical parameters.

Materials and methods

The study consisted of two groups: healthy individuals (control: n = 24), and generalized Stage III Grade B periodontitis (P: n = 21). Clinical periodontal parameters (probing pocket depth, bleeding on probing, clinical attachment level) were recorded. IL 6 and NOS levels in saliva and serum were analyzed by enzyme-linked immunosorbent assay (ELISA). ADMA, SDMA, homoArg, arginine, and L-NMMA in saliva and serum were analyzed by liquid chromatography–mass spectrometry (LC MS/MS).

Results

Clinical parameters were significantly higher in the periodontitis group (p < 0.001). In periodontitis group, NOS, ADMA, and arginine levels in saliva were statistically significantly higher than control group (p < 0.05). Serum levels of SDMA were statistically significantly lower, and IL-6 was statistically significantly higher in P group than C group (p < 0.05). ADMA, NOS, and arginine levels were significantly positive correlated with all clinical periodontal parameters (p < 0.05).

Conclusions

These findings suggest that there is a relationship between severity of periodontal disease and endothelial dysfunction by means of ADMA. Salivary ADMA may be related with periodontal inflammation.

Clinical relevance

ADMA levels in periodontal inflammation are associated with endothelial dysfunction. According to the results of our study, periodontal inflammation is effective on both local and systemic methylated arginine metabolites and nitric oxide synthase levels. This may shed light on the relationship between periodontal disease and systemic status.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. William’s probe, Hu-Friedy, Chicago, IL.

  2. Human IL-6 ELISA Kit, Uscn, Cloud-Clone Corp, USA and Human NOS1 ELISA Kit, Uscn, Cloud-Clone Corp, USA.

  3. Synergy HT Microplate Reader, Bio-Tek Instruments, Winooski, WT, USA.

  4. TSQ Quantum Access MAX Triple Stage Quadrupole Mass, Thermo Scientific, USA.

  5. 3.1.9.2 G*Power; https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-undarbeitspsychologie/gpower.html.

  6. SPSS for Windows v.26, IBM SPSS Inc., New York, NY, USA.

References

  1. Lowenstein CJ, Snyder SH (1992) Nitric oxide A novel biologic messenger. Cell 70(5):705–707. https://doi.org/10.1016/0092-8674(92)90301-r

    Article  PubMed  Google Scholar 

  2. Moncada S, Palmer RM, Higgs E (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43(2):109–142

    PubMed  Google Scholar 

  3. Stuehr DJ, Griffith OW (1992) Mammalian nitric oxide synthase. Adv Enzymol 65:287–331. https://doi.org/10.1002/9780470123119.ch8

    Article  PubMed  Google Scholar 

  4. Lowenstein CJ, Dinerman JL, Snyder SH (1994) Nitric oxide: a physiologic messenger. Ann Intern Med 120(3):227–237. https://doi.org/10.7326/0003-4819-120-3-199402010-00009

    Article  PubMed  Google Scholar 

  5. Bogdan C (2015) Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol 36(3):161–178. https://doi.org/10.1016/j.it.2015.01.003

    Article  PubMed  Google Scholar 

  6. Lundberg JO, Gladwin MT, Weitzberg E (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14(9):623–641. https://doi.org/10.1038/nrd4623

    Article  PubMed  Google Scholar 

  7. Quillon A, Fromy B (2015) Debret R (2015) Endothelium microenvironment sensing leading to nitric oxide mediated vasodilation: a review of nervous and biomechanical signals. Nitric Oxide 45:20–26. https://doi.org/10.1016/j.niox.2015.01.006

    Article  PubMed  Google Scholar 

  8. Demir B, Demir S, Pasa S (2012) The role of homocysteine, asymmetric dimethylarginine and nitric oxide in preeclampsia. J Obstet Gynaecol 32(6):525–528. https://doi.org/10.3109/01443615.2012.693985

    Article  PubMed  Google Scholar 

  9. Ignarro LJ (1990) Nitric oxide. A novel signal transduction mechanism for transcellular communication. Hypertension 16(5):477–483. https://doi.org/10.1161/01.hyp.16.5.477

    Article  PubMed  Google Scholar 

  10. Cooke JP, Rossitch JRE, Andon NA, Loscalzo J, Dzau VJ (1991) Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 88(5):1663–1671. https://doi.org/10.1172/JCI115481

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tsao PS, Buitrago R, Chan JR, Cooke JP (1996) Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1. Circulation 94(7):1682–1689. https://doi.org/10.1161/01.cir.94.7.1682

    Article  PubMed  Google Scholar 

  12. Muhl H, Sandau K, Brune B, Briner VA, Pfeilschifter J (1996) Nitric oxide donors induce apoptos is in glomerular mesangial cells, epithelial cells and endothelial cells. Eur J Pharmacol 317(1):137–149. https://doi.org/10.1016/s0014-2999(96)00701-7

    Article  PubMed  Google Scholar 

  13. Moura MF, Navarro TP, Silva TA, Cota LOM, Soares Dutra Oliveira AM, Costa FO (2017) Periodontitis and endothelial dysfunction: periodontal clinical parameters and levels of salivary markers interleukin-1β, tumor necrosis factor-α, matrix metalloproteinase-2, tissue inhibitor of metalloproteinases-2 complex, and nitric oxide. J Periodontol 88(8):778–787. https://doi.org/10.1902/jop.2017.170023

    Article  PubMed  Google Scholar 

  14. Vallance P, Leiper J (2004) Cardiovascular biology of asymmetric dimetylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 24(6):1023–1030. https://doi.org/10.1161/01.ATV.0000128897.54893.26

    Article  PubMed  Google Scholar 

  15. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, Berka V, Zweier JL (2007) Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem 282(2):879–887. https://doi.org/10.1074/jbc.M603606200

    Article  PubMed  Google Scholar 

  16. Sobczak A, Prokopowicz A, Radek M, Szula M, Zaciera M, Kurek J, Goniewicz ML (2014) Tobacco smoking decreases plasma concentration of the emerging cardiovascular risk marker. L-homoarginine Circ J 78(5):1254–1258. https://doi.org/10.1253/circj.cj-13-1334

    Article  PubMed  Google Scholar 

  17. Isola G, Alibrandi A, Currò M, Matarese M, Ricca S, Matarese G, Ientile R, Kocher T (2020) Evaluation of salivary and serum ADMA levels in patients with periodontal and cardiovascular disease as subclinical marker of cardiovascular risk. J Periodontol. https://doi.org/10.1002/JPER.19-0446. Online ahead of print.

  18. Dimitroulas T, Hodson J, Sandoo A, Smith J, Kitas GD (2017) Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation. Arthritis Res Ther 19(1):32. https://doi.org/10.1186/s13075-017-1232-1

    Article  PubMed  PubMed Central  Google Scholar 

  19. Winkler MS, Kluge S, Holzmann M, Moritz E, Robbe L, Bauer A, Zahrte C, Priefler M, Schwedhelm E, Böger RH, Goetz AE, Nierhaus A, Zoellner C (2017) Markers of nitric oxide are associated with sepsis severity: an observational study. Crit Care 21(1):189. https://doi.org/10.1186/s13054-017-1782-2

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vallance P, Chan N (2001) Endothelial function and nitric oxide: clinical relevance. Heart 85(3):342–350. https://doi.org/10.1136/heart.85.3.342

    Article  PubMed  PubMed Central  Google Scholar 

  21. Almeida S, Figueredo CM, Lemos C, Bregman R, Fischer RG (2017) Periodontal treatment in patients with chronic kidney disease: a pilot study. J Period Res 52(2):262–267. https://doi.org/10.1111/jre.12390

    Article  Google Scholar 

  22. Tonetti MS, Greenwell H, Kornman KS (2018) Staging and grading of periodontitis: framework and proposal of a new classification and case definition. Review J Periodontol 89(1):159–172. https://doi.org/10.1111/jcpe.12945

    Article  Google Scholar 

  23. Buduneli N, Kardesler L, Isik H, Willis CS 3rd, Hawkins SI, Kinane DF, Scott DA (2006) Effects of smoking and gingival inflammation on salivary antioxidant capacity. J Clin Periodontol 33:159–164. https://doi.org/10.1111/j.1600-051X.2006.00892.x

    Article  PubMed  Google Scholar 

  24. Di Gangi IM, Chiandetti L, Gucciardi A, Moret V, Naturale M, Giordano G (2010) Simultaneous quantitative determination of N(G), N(G)-dimethyl-L-arginine or asymmetric dimethylarginine and related pathway’s metabolites in biological fluids by ultrahigh-performance liquid chromatography/electrospray ionization-tandem mass spectrometry. Anal Chim Acta 677(2):140–148. https://doi.org/10.1016/j.aca.2010.08.011

    Article  PubMed  Google Scholar 

  25. Azuma MM, Jamuel RO, Gomes-Filho JE, Dezan-Junior E, Cintra LTA (2014) The role IL-6 on apical periodontitis: a systematic review. Int Endod J 47(7):615–621. https://doi.org/10.1111/iej.12196

    Article  PubMed  Google Scholar 

  26. Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A (2014) eNOS uncoupling in cardiovascular diseases—the role of oxidative stress and inflammation. Curr Pharm Des 20(22):3579–3594. https://doi.org/10.2174/13816128113196660748

    Article  PubMed  Google Scholar 

  27. Koh KP, Wang Y, Yi T, Shiao SL, Lorber MI, Sessa WC, Tellides G, Pober JS (2004) T cell-mediated vascular dysfunction of human allografts results from IFN-gamma dysregulation of NO synthase. J Clin Invest 114(6):846–856. https://doi.org/10.1172/JCI21767

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lai PF, Mohamed F, Monge JC, Stewart DJ (2003) Down-regulation of eNOS mRNA expression by TNF alpha: identification and functional characterization of RNA-protein interactions in the 3’UTR. Cardiovascular Res 59(1):160–168. https://doi.org/10.1016/s0008-6363(03)00296-7

    Article  Google Scholar 

  29. Bouras G, Deftereos S, Tousoulis D, Giannopoulos G, Chatzis G, Tsounis D, Cleman MW, Stefanadis C (2013) ADMA: a promising biomarker for cardiovascular disease? Curr Top Med Chem 13(2):180–200. https://doi.org/10.2174/1568026611313020007

    Article  PubMed  Google Scholar 

  30. Kim JH, Yoo BC, Yang WS, Kim E, Hong S, Cho JY (2016) The role of protein arginine methyltransferases in inflammatory responses. Mediators Inflamm 2016:4028353. https://doi.org/10.1155/2016/4028353

    Article  PubMed  PubMed Central  Google Scholar 

  31. Krzystek-Korpacka M, Wisniewski J, Fleszar FG, Bednarz-Misa I, Bronowicka-Szydełko A, Gacka M, Masłowski L, Kędzior K, Witkiewicz W (2019) Gamian A (2019) Metabolites of the NO pathway are altered and indicative of reduced NO and arginine bioavailability in patients with cardiometabolic diseases complicated with chronic wounds of lower extremities: targeted metabolomics approach. Oxid Med Cell Longev 2019:5965721. https://doi.org/10.1155/2019/5965721.eCollection

    Article  PubMed  PubMed Central  Google Scholar 

  32. Karşıyaka-Hendek M, Olgun E, Kısa Ü (2019) Effect of initial periodontal treatment on cardiovascular risk markers in patients with severe chronic periodontitis. Meandros Med Dent J 20:114–120. https://doi.org/10.4274/meandros.galenos.2018.58661

    Article  Google Scholar 

  33. Tsikas D, Bollenbach A, Hanff E, Arinc Kayacelebi A (2018) Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and homoarginine (hArg): the ADMA. SDMA and hArg paradoxes Cardiovasc Diabetol 17:1. https://doi.org/10.1186/s12933-017-0656-x

    Article  PubMed  Google Scholar 

  34. McDonald KK, Zharikov S, Block ER, Kilberg MS (1997) A caveolar complex between the cationic amino acid transport I and endothelial nitric oxide synthase may explain the arginine paradox. J Biol Chem 272(50):31213–31216. https://doi.org/10.1074/jbc.272.50.31213

    Article  PubMed  Google Scholar 

  35. Hibbs JB Jr, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235(4787):473–476. https://doi.org/10.1126/science.2432665

    Article  PubMed  Google Scholar 

  36. Michel T (2013) R is for arginine: metabolism of arginine takes off again, in new directions. Circulation 128(13):1400–1404. https://doi.org/10.1161/CIRCULATIONAHA.113.005924

    Article  PubMed  PubMed Central  Google Scholar 

  37. Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JSA, Heiskanen N, Vanninen E, Punnonen K, Heinonen S (2008) Serum L-homoarginine is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72(11):1879–1884. https://doi.org/10.1253/circj.cj-08-0240

    Article  PubMed  Google Scholar 

  38. Gustafsson A, Asman B (1996) Increased release of free oxygen radicals from peripheral neutrophils in adult periodontitis after fc delta-receptor stimulation. J Clin Periodontol 23(1):38–44. https://doi.org/10.1111/j.1600-051x.1996.tb00502.x

    Article  PubMed  Google Scholar 

  39. Key LL Jr, Wolf WC, Gundberg CM, Ries WL (1994) Superoxide and bone resorption. Bone 15(4):431–436. https://doi.org/10.1016/8756-3282(94)90821-4

    Article  PubMed  Google Scholar 

  40. Landim MBP, Filho AC, Chagas CP (2009) Asymmetric dimethylarginine (ADMA) and endothelial dysfunction: implications for atherogenesis. Clinics 64(5):471–478. https://doi.org/10.1590/s1807-59322009000500015

    Article  PubMed  PubMed Central  Google Scholar 

  41. Böger RH (2003) When the endothelium cannot say ‘NO’ anymore. ADMA, an endogenous inhibitor of NO synthase, promotes cardiovascular disease. Eur Heart J 24(21):1901–1902. https://doi.org/10.1016/j.ehj.2003.08.010

    Article  PubMed  Google Scholar 

  42. Sydow K, Schwedhelm E, Arakawa N, Bode-Böger SM, Tsikas D, Hornig B, Frölich JC, Böger RH (2003) ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res 57(1):244–252. https://doi.org/10.1016/s0008-6363(02)00617-x

    Article  PubMed  Google Scholar 

  43. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87(10):840–844. https://doi.org/10.1161/01.res.87.10.840

    Article  PubMed  Google Scholar 

  44. Antoniades C, Tousoulis D, Marinou K, Vasiliadou C, Tentolouris C, Bouras G, Pitsavos C, Stefanadis C (2006) Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines. Am J Clin Nutr 84(4):781–788. https://doi.org/10.1093/ajcn/84.4.781

    Article  PubMed  Google Scholar 

  45. Cardounel AJ, Zweier JL (2002) Endogenous methylarginines regulate neuronal nitric-oxide synthase and prevent excitotoxic injury. J Biol Chem 277(37):33995–34002. https://doi.org/10.1074/jbc.M108983200

    Article  PubMed  Google Scholar 

  46. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339(8793):572–576. https://doi.org/10.1016/0140-6736(92)90865-z

    Article  PubMed  Google Scholar 

  47. Ross R, Gillitzer C, Kleinz R, Schwing J, Kleinert H, Förstermann U, Reske-Kunz AB (1998) Involvement of NO in contact hypersensitivity. Int Immunol 10(1):61–90. https://doi.org/10.1093/intimm/10.1.61

    Article  PubMed  Google Scholar 

  48. Hussain QA, McKay IJ, Gonzales-Marin C, Allaker RP (2016) Detection of adrenomedullin and nitric oxide in different forms of periodontal disease. J Periodontal Res 51(1):16–25. https://doi.org/10.1111/jre.12273

    Article  PubMed  Google Scholar 

  49. Andrukhov O, Haririan H, Bertl K, Rausch WD, Bantleon HP, Moritz A, Rausch-Fan X (2013) Nitric oxide production, systemic inflammation and lipid metabolism in periodontitis patients: possible gender aspect. J Clin Periodontol 40(10):916–923. https://doi.org/10.1111/jcpe.12145

    Article  PubMed  Google Scholar 

  50. Önder C, Kurgan Ş, Altıngöz SM, Bağış N, Uyanık M, Serdar MA, Kantarcı A, Günhan M (2017) Impact of non-surgical periodontal therapy on saliva and serum levels of markers of oxidative stress. Clin Oral Investig 21(6):1961–1969. https://doi.org/10.1007/s00784-016-1984-z

    Article  PubMed  Google Scholar 

  51. Tripathi P, Tripathi P, Kashyap L, Singh V (2007) The role of nitric oxide in inflammatory reactions. FEMS Immunol Med Microbiol 51(3):443–452. https://doi.org/10.1111/j.1574-695X.2007.00329.x

    Article  PubMed  Google Scholar 

  52. Emrich IE, Zawada AM, Martens- Lobenhoffer J, Fliser D, Wagenpfeil S, Heine GH, Bode-Böger SM (2017) Symmetric dimethylarginine (SDMA) outperforms ADMA and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease. Clin Res Cardiol 107(3):201–213. https://doi.org/10.1007/s00392-017-1172-4

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by the Ankara University Department of Periodontology.

Author information

Authors and Affiliations

  1. Department of Periodontology, Faculty of Dentistry, Ankara University, 06500-Cankaya, Ankara, Turkey

    Volkan Şengül, Şivge Kurgan, Canan Önder & Meral Günhan

  2. Department of Periodontology, Faculty of Dentistry, Yozgat Bozok University, Yozgat, Turkey

    Zeliha Güney

  3. Department of Medical Biochemistry, School of Medicine, Acıbadem University, İstanbul, Turkey

    Muhittin A. Serdar

Authors
  1. Volkan Şengül
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeliha Güney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Şivge Kurgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Canan Önder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muhittin A. Serdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meral Günhan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Şivge Kurgan.

Ethics declarations

Ethics approval

The present study was approved by the human subject’s ethics board of Ankara University (No: 09/01, on 24.07.2019) for use and access of human subjects in research and was performed according to the Helsinki Declaration.

Consent to participate

All participants have given written consent before the study.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Şengül, V., Güney, Z., Kurgan, Ş. et al. Evaluation of salivary and serum methylated arginine metabolites and nitric oxide synthase in advanced periodontitis patients. Clin Oral Invest 26, 5061–5070 (2022). https://doi.org/10.1007/s00784-022-04479-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-022-04479-w

Keywords

Search

Navigation