Abstract
Objectives
The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA.
Materials and methods
Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3 months after MAD.
Results
Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3 months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393–0.748]) to (0.708 [0.533–0.893]) and SIRT1 protein levels in PBMC increased from 0.58 ± 0.23 pg/μg of total protein to 0.95 ± 0.26 pg/μg of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low.
Conclusions
Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC.
Clinical relevance
LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.
Similar content being viewed by others
References
Lavie L (2003) Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Med Rev 7:35–51
Busse R, Fleming I (1995) Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 27:331–340
Pankow W, Lies A, Lohmann FW (2000) Sleep-disordered breathing and hypertension. N Engl J Med 343:966
Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS (2002) Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 165:670–676
Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J (2002) Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 166:159–165
De Boeck G, Forsyth RG, Praet M, Hogendoorn PC (2009) Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 217:327–344
Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, Maitre B, Sarni M, Housset B, Weitzenblum E, Matrat M, Le Corvoisier P, Rideau D, Boczkowski J, Dubois-Randé JL, Chouaid C, Adnot S (2009) Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 179:566–571
Blackburn EH, Epel ES, Lin J (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350:1193–1198
Yao H, Rahman I (2012) Perspectives on translational and therapeutic aspects of SIRT1 in inflammaging and senescence. Biochem Pharmacol 84:1332–1339
Zeng L, Chen R, Liang F, Tsuchiya H, Murai H, Nakahashi T, Iwai K, Takahashi T, Kanda T, Morimoto S (2009) Silent information regulator, Sirtuin 1, and age-related diseases. Geriatr Gerontol Int 9:7–15
Ota H, Eto M, Ogawa S, Iijima K, Akishita M, Ouchi Y (2010) SIRT1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis. J Atheroscler Thromb17:431–435
Weaver TE, Grunstein RR (2008) Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 5:173–178
Chan AS, Lee RW, Cistulli PA (2008) Non-positive airway pressure modalities: mandibular advancement devices/positional therapy. Proc Am Thorac Soc 5:179–184
Lim J, Lasserson TJ, Fleetham J, Wright J (2004) Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 4:CD004435
Iber C, Ancoli-Israel S, Chesson AL, Quan SF (2007) The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications, 1st edn. American Academy of Sleep Med, Westchester
Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47–e447
Barceló A, Piérola J, López-Escribano H, de la Peña M, Soriano JB, Alonso-Fernández A, Ladaria A, Agustí A (2010) Telomere shortening in sleep apnea syndrome. Respir Med 104:1225–1229
LIN L, LI TP (2011) Alteration of telomere length of the peripheral white blood cells in patients with obstructive sleep apnea syndrome. Nan Fang Yi Ke Da Xue Xue Bao 31:457–460
Tempaku PF, Mazzotti DR, Hirotsu C, Andersen ML, Xavier G, Maurya PK, Rizzo LB, Brietzke E, Belangero SI, Bittencourt L, Tufik S (2016) The effect of the severity of obstructive sleep apnea syndrome on telomere length. Oncotarget 7:69216–69224
Savolainen K, Eriksson JG, Kajantie E, Lahti M, Räikkönen K (2014) The history of sleep apnea is associated with shorter leukocyte telomere length: the Helsinki birth cohort study. Sleep Med 15:209–212
Riestra P, Gebreab SY, Xu R, Khan RJ, Quarels R, Gibbons G, Davis SK (2017) Obstructive sleep apnea risk and leukocyte telomere length in African Americans from the MH-GRID study. Sleep Breath 21:751–757
Chen WJ, Liaw SF, Lin CC, Chiu CH, Lin MW, Chang FT (2015) Effect of nasal CPAP on SIRT1 and endothelial function in obstructive sleep apnea syndrome. Lung 193:1037–1045
Wang Q, Sun X, Li X, Dong X, Li P, Zhao L (2015) Resveratrol attenuates intermittent hypoxia-induced insulin resistance in rats: involvement of Sirtuin 1 and the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway. Mol Med Rep 11:151–158
Kagawa Y (2012) From clock genes to telomeres in the regulation of the healthspan. Nutr Rev 70:459–471
Pieters N, Janssen BG, Valeri L, Cox B, Cuypers A, Dewitte H, Plusquin M, Smeets K, Nawrot TS (2015) Molecular responses in the telomere-mitochondrial axis of ageing in the elderly: a candidate gene approach. Mech Ageing Dev 145:51–57
De Bonis ML, Ortega S, Blasco MA (2014) SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells. Stem Cell Reports 2:690–706
Kim KS, Kwak JW, Lim SJ, Park YK, Yang HS, Kim HJ (2016) Oxidative stress-induced telomere length shortening of circulating leukocyte in patients with obstructive sleep apnea. Aging Dis 7:604–613
Boyer L, Audureau E, Margarit L, Marcos E, Bizard E, Le Corvoisier P, Macquin-Mavier I, Derumeaux G, Damy T, Drouot X, Covali-Noroc A, Boczkowski J, Bastuji-Garin S, Adnot S (2016) Telomere shortening in middle-aged men with sleep-disordered breathing. Ann Am Thorac Soc 13:1136–1143
Kwon AM, Baik I, Thomas RJ, Shin C (2015) The association between leukocyte telomere lengths and sleep instability based on cardiopulmonary coupling analysis. Sleep Breath 19:963–968
Prather AA, Gurfein B, Moran P, Daubenmier J, Acree M, Bacchetti P, Sinclair E, Lin J, Blackburn E, Hecht FM, Epel ES (2015) Tired telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women. Brain Behav Immun 47:155–162
Choi KM, Thomas RJ, Yoon DW, Lee SK, Baik I, Shin C (2016) Interaction between obstructive sleep apnea and shortened telomere length on brain white matter abnormality. Sleep 39:1639–1645
Marin JM, Carrizo SJ, Vicente E, Agusti AG (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365:1046–1053
Alonso-Fernández A, García-Río F, Arias MA, Hernanz A, de la Peña M, Piérola J, Barceló A, López-Collazo E, Agustí A (2009) Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax 64:581–586
Barnes M, McEvoy RD, Banks S, Tarquinio N, Murray CG, Vowles N, Pierce RJ (2004) Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 170:656–664
Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G (2007) The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 131:740–749
Acknowledgments
We would like to acknowledge the help with statistics from Ms. Fang-Ju Sun of Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
Funding
This work was supported by a grant from the Ministry of Science and Technology (Grant MOST 103-2314-B-303-014-MY2).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consents
Informed consent was obtained from all individual study participants.
Rights and permissions
About this article
Cite this article
Lin, CC., Wang, HY., Liaw, SF. et al. Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea. Clin Oral Invest 23, 1397–1405 (2019). https://doi.org/10.1007/s00784-018-2560-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00784-018-2560-5