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.
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Notes
William’s probe, Hu-Friedy, Chicago, IL.
Human IL-6 ELISA Kit, Uscn, Cloud-Clone Corp, USA and Human NOS1 ELISA Kit, Uscn, Cloud-Clone Corp, USA.
Synergy HT Microplate Reader, Bio-Tek Instruments, Winooski, WT, USA.
TSQ Quantum Access MAX Triple Stage Quadrupole Mass, Thermo Scientific, USA.
SPSS for Windows v.26, IBM SPSS Inc., New York, NY, USA.
References
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
Moncada S, Palmer RM, Higgs E (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43(2):109–142
Stuehr DJ, Griffith OW (1992) Mammalian nitric oxide synthase. Adv Enzymol 65:287–331. https://doi.org/10.1002/9780470123119.ch8
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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The study was supported by the Ankara University Department of Periodontology.
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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.
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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
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DOI: https://doi.org/10.1007/s00784-022-04479-w