Skip to main content

Advertisement

SpringerLink
Log in

Magnesium Supplementation Affects the Expression of Sirtuin1, Tumor Protein P53 and Endothelial Nitric Oxide Synthase Genes in Patients with Atherosclerosis: A Double-Blind, Randomized, Placebo-Controlled Trial

  • Original Research Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

Magnesium seems to play a role in improving cardiovascular function, but its exact mechanism is unknown. In this study, we hypothesized that magnesium could modulate the expression of genes involved in atherosclerosis. The aim of the present investigation was to evaluate the effect of magnesium sulfate on the expression of sirtuin1 (SIRT1), tumor protein p53 (TP53), and endothelial nitric oxide synthase (eNOS) genes in patients with atherosclerosis. This study was a placebo-controlled double-blind randomized clinical trial on 56 patients with angiographically proven atherosclerosis. Participants were randomly divided into two groups receiving 300 mg/day magnesium sulfate (n = 29) and placebo (n = 27) for three months (following up every month). Fasting blood samples were taken before and after the intervention and total RNA was extracted and used to evaluate the expression level of SIRT1, TP53, and eNOS genes by Real-Time PCR. The expression of eNOS gene was significantly increased (P < 0.0001) and the expression of TP53 gene was decreased (P = 0.02) in the magnesium sulfate group compared to the placebo group. But SIRT1 gene expression was not significantly different between the two groups. Our findings demonstrate that magnesium sulfate supplementation may have a protective role against the progression of atherosclerosis through upregulation of eNOS and downregulation of TP53 gene.

Trial registration: This present clinical trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the registration code of “IRCT20151028024756N3”, https://www.irct.ir/trial/29097?revision=114102. Registered on 16 December 2019.

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

Data Availability

The data are available from the corresponding author on reasonable request.

References

  1. Yuan HQ, Hao YM, Ren Z, Gu HF, Liu FT, Yan BJ, et al. Tissue factor pathway inhibitor in atherosclerosis. Clin Chim Acta. 2019;491:97–102. https://doi.org/10.1016/j.cca.2019.01.024.

    Article  CAS  Google Scholar 

  2. Ong ALC, Ramasamy TS. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev. 2018;43:64–80. https://doi.org/10.1016/j.arr.2018.02.004.

    Article  CAS  Google Scholar 

  3. Martinez PF, Okoshi MP. Genetic risk in coronary artery disease. Arq Bras Cardiol. 2018;111(1):62–3. https://doi.org/10.5935/abc.20180130.

    Article  Google Scholar 

  4. Yang X, Li Y, Li Y, Ren X, Zhang X, Hu D, et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol. 2017;23(8):600. https://doi.org/10.3389/fphys.2017.00600.

    Article  Google Scholar 

  5. Chiriacò M, Georgiopoulos G, Duranti E, Antonioli L, Puxeddu I, Nannipieri M, et al. Inflammation and vascular ageing: from telomeres to novel emerging mechanisms. High Blood Press Cardiovasc Prev. 2019;26(4):321–9. https://doi.org/10.1007/s40292-019-00331-7.

    Article  Google Scholar 

  6. D’Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxid Redox Signal. 2018;28(8):711–732. doi: https://doi.org/10.1089/ars.2017.7178. Epub 2017.

  7. Ma L, Li Y. SIRT1: role in cardiovascular biology. Clin Chim Acta. 2015;440:8–15. https://doi.org/10.1016/j.cca.2014.10.036.

    Article  CAS  Google Scholar 

  8. Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015;36(48):3404–12. https://doi.org/10.1093/eurheartj/ehv290

  9. Kitada M, Ogura Y, Koya D. The protective role of Sirt1 in vascular tissue: Its relationship to vascular aging and atherosclerosis. Aging (Albany NY). 2016;8(10):2290–2307. https://doi.org/10.18632/AGING.101068.

  10. Finkel T, Deng C-X, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460(7255):587–91. https://doi.org/10.1038/nature08197.

    Article  CAS  Google Scholar 

  11. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell. 2001;107(2):137–48. https://doi.org/10.1016/S0092-8674(01)00524-4.

    Article  CAS  Google Scholar 

  12. Hori YS, Kuno A, Hosoda R, Horio Y. Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS ONE. 2013;8(9):13–5. https://doi.org/10.1371/journal.pone.0073875.

    Article  CAS  Google Scholar 

  13. Ota H, Eto M, Ogawa S, Iijima K, Akishita M, Ouchi Y. Sirt1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis. J Atheroscler Thromb. 2010;17:431–5. https://doi.org/10.5551/jat.3525.

    Article  CAS  Google Scholar 

  14. Stein S, Matter CM. Protective roles of SIRT1 in atherosclerosis. Cell Cycle. 2011;10(4):640–7. https://doi.org/10.4161/cc.10.4.14863.

    Article  CAS  Google Scholar 

  15. Winnik S, Stein S, M Matter C. SIRT1-an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis. Curr Vasc Pharmacol. 2012;10(6):693–6. https://doi.org/10.2174/157016112803520756.

  16. Fazlali M, Kharazmi F, Kamran M, Malekzadeh K, Talebi A, Khosravi F, et al. Effect of oral magnesium sulfate administration on lectin-like oxidized low-density lipoprotein receptor-1 gene expression to prevent atherosclerosis in diabetic rat vessels. J Diabetes Investig. 2019;10(3):650–8. https://doi.org/10.1111/jdi.12961.

    Article  CAS  Google Scholar 

  17. Maier JA, Bernardini D, Rayssiguier Y, Mazur A. High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. Biochim Biophys Acta (BBA)-Molecular Basis Dis. 2004;1689(1):6–12. https://doi.org/10.1016/j.bbadis.2004.02.004..

  18. Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and sirtuin 3: Physiological modulators of metabolism. Physiol Rev. 2012;92:1479–514. https://doi.org/10.1152/physrev.00022.2011.

    Article  CAS  Google Scholar 

  19. Ha BG, Moon DS, Kim HJ, Shon YH. Magnesium and calcium-enriched deep-sea water promotes mitochondrial biogenesis by AMPK-activated signals pathway in 3T3-L1 preadipocytes. Biomed Pharmacother. 2016;83:477–84. https://doi.org/10.1016/j.biopha.2016.07.009.

    Article  CAS  Google Scholar 

  20. Okazaki T, Mochizuki T, Tashima M, Sawada H, Uchino H. Magnesium deprivation inhibits the expression of differentiation-related phenotypes in human promyelocytic leukemia HL-60 cells. J Cell Physiol. 1987;131(1):50–7. https://doi.org/10.1002/jcp.1041310109.

    Article  CAS  Google Scholar 

  21. Martins IJ (2016) Magnesium therapy prevents senescence with the reversal of diabetes and Alzheimer's disease. Health 8(7):694–710. https://doi.org/10.4236/health.2016.87073.

    Article  CAS  Google Scholar 

  22. Afshar Ebrahimi F, Foroozanfard F, Aghadavod E, Bahmani F, Asemi Z. The effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress, and gene expression related to inflammation in polycystic ovary syndrome: a randomized controlled clinical trial. Biol Trace Elem Res. 2018;184(2):300–7. https://doi.org/10.1007/s12011-017-1198-5.

    Article  CAS  Google Scholar 

  23. Joris PJ, Plat J, Bakker SJ, Mensink RP. Effects of long-term magnesium supplementation on endothelial function and cardiometabolic risk markers: a randomized controlled trial in overweight/obese adults. Sci Rep. 2017;7(1):1–7. https://doi.org/10.1038/s41598-017-00205-9.

    Article  CAS  Google Scholar 

  24. Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Circulation. 2000;102(19):2353–8. https://doi.org/10.1161/01.cir.102.19.2353.

    Article  CAS  Google Scholar 

  25. Kolte D, Vijayaraghavan K, Khera S, Sica DA, Frishman WH. Role of magnesium in cardiovascular diseases. Cardiol Rev. 2014;22(4):182–92. https://doi.org/10.1097/CRD.0000000000000003.

    Article  Google Scholar 

  26. Arunachalam G, Yao H, Sundar IK, Caito S, Rahman I. SIRT1 regulates oxidant-and cigarette smoke-induced eNOS acetylation in endothelial cells: role of resveratrol. Biochem Biophys Res Commun. 2010;393(1):66–72. https://doi.org/10.1016/j.bbrc.2010.01.080.

    Article  CAS  Google Scholar 

  27. Baccarani M, Pane F, Saglio G. Monitoring treatment of chronic myeloid leukemia. Haematologica. 2008;93(2):161–9. https://doi.org/10.3324/haematol.12588.

    Article  CAS  Google Scholar 

  28. Kung C-P, Murphy ME. The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol. 2016;231(2):R61–75. https://doi.org/10.1530/JOE-16-032.

    Article  CAS  Google Scholar 

  29. Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol. 2007;43(5):571–9. https://doi.org/10.1016/j.yjmcc.2007.08.008.

    Article  CAS  Google Scholar 

  30. Abiri B, Sarbakhsh P, Vafa M. Randomized study of the effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammation, and SIRT1 in obese women with mild to moderate depressive symptoms. Nutr Neurosci [Internet]. 2021;0(0):1–13. Available from: https://doi.org/10.1080/1028415X.2021.1945859

  31. Altura BM, Shah NC, Li Z, Jiang XC, Zhang A, Li W, et al. Short-term magnesium deficiency upregulates sphingomyelin synthase and p53 in cardiovascular tissues and cells: Relevance to the de novo synthesis of ceramide. Am J Physiol - Hear Circ Physiol. 2010;299(6):2046–55. https://doi.org/10.1152/ajpheart.00671.2010.

    Article  CAS  Google Scholar 

  32. Tabas I. P53 and atherosclerosis. Circ Res. 2001;88:747–9. https://doi.org/10.1161/hh0801.090536.

    Article  CAS  Google Scholar 

  33. Hong FF, Liang XY, Liu W, Lv S, He SJ, Kuang HB, et al. Roles of eNOS in atherosclerosis treatment. Inflamm Res. 2019;68(6):429–41. https://doi.org/10.1007/s00011-019-01229-9.

    Article  CAS  Google Scholar 

  34. Sigala F, Efentakis P, Karageorgiadi D, Filis K, Zampas P, Iliodromitis EK, et al. Redox biology reciprocal regulation of eNOS, H 2 S and CO-synthesizing enzymes in human atheroma: correlation with plaque stability and e ff ects of simvastatin. Redox Biol. 2017;12:70–81. https://doi.org/10.1016/j.redox.2017.02.006.

    Article  CAS  Google Scholar 

  35. Ning K, Wang MJ, Lin G, Zhang YL, Li MY, Yang BF, et al. eNOS-NO system contributes to a novel anti-atherogenic effect of Leonurine via inflammation inhibition and plaque stabilization. J Pharmacol Exp Ther. 2020;373(3):463–75. https://doi.org/10.1124/jpet.119.264887.

    Article  CAS  Google Scholar 

  36. Magenta A, Sileno S, D’Agostino M, Persiani F, Beji S, Paolini A, et al. Atherosclerotic plaque instability in carotid arteries: miR-200c as a promising biomarker. Clin Sci. 2018;132(22):2423–36. https://doi.org/10.1042/CS20180684.

    Article  CAS  Google Scholar 

  37. Badimon L, Peña E, Arderiu G, Padró T, Slevin M, Vilahur G, et al. C-reactive protein in atherothrombosis and angiogenesis. Front Immunol. 2018;2(9):430. https://doi.org/10.3389/fimmu.2018.00430.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was extracted from Behnaz Rahnama Inchehsablagh thesis, submitted to Hormozgan University of Medical Sciences in partial fulfillment of the requirements for the Ms.c in Medical physiology. This work was supported by a grant from the Vice Chancellor for Research, Hormozgan University of Medical Sciences.

Funding

This research has been funded by the Hormozgan University of medical sciences.

Author information

Authors and Affiliations

  1. Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Behnaz Rahnama Inchehsablagh

  2. Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Farhad Ghadiri Soufi, Shabnaz Koochakkhani & Fariba Azarkish

  3. Cardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Hossein Farshidi & Mahdiye Eslami

  4. Clinical Research Development Center of Shahidmohammadi Hospital, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Masoumeh Mahmoodi

  5. Physiology Department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Nepton Soltani

  6. Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

    Ebrahim Eftekhar

Authors
  1. Behnaz Rahnama Inchehsablagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farhad Ghadiri Soufi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shabnaz Koochakkhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fariba Azarkish
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hossein Farshidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mahdiye Eslami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masoumeh Mahmoodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nepton Soltani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ebrahim Eftekhar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ebrahim Eftekhar.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

This research has been approved by the University Ethics Committee (IR.HUMS.REC.1398.295).

Consent to Participate

All participants were given informed consent and were properly informed of the procedure.

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

Rahnama Inchehsablagh, B., Ghadiri Soufi, F., Koochakkhani, S. et al. Magnesium Supplementation Affects the Expression of Sirtuin1, Tumor Protein P53 and Endothelial Nitric Oxide Synthase Genes in Patients with Atherosclerosis: A Double-Blind, Randomized, Placebo-Controlled Trial. Ind J Clin Biochem 38, 59–66 (2023). https://doi.org/10.1007/s12291-022-01032-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-022-01032-0

Keywords

Search

Navigation