Abstract
Purpose
To evaluate the effect of oral magnesium sulfate (MgSO4) on the gene expression and serum levels of inflammatory cytokines including TNF-α, IL-18, IL-1β, IL-6, and IFN-γ in patients with moderate coronary artery disease (CAD).
Methods
60 CAD patients were selected based on angiography findings and were randomly divided into two groups that received 300 mg/day MgSO4 (n = 30) or placebo (n = 30) for 3 months. Gene expression and serum levels of inflammatory cytokines were assessed.
Results
After 3 months of intervention, gene expression and serum levels of IL-18 and TNF-α in the MgSO4 group were significantly less than the placebo group (P < 0.05). However, no significant difference in gene expression and serum levels of IL-1β, IL-6, and IFN-γ was observed between the two groups (P > 0.05). In addition, within group analysis demonstrate that Mg-treatment significantly decrease serum level of TNF-α and IL-18 as compared to pretreatment.
Conclusion
The results of our study demonstrate that 3-month magnesium sulfate administration (300 mg/day) to CAD patients could significantly decrease serum concentration and gene expression levels of IL-18 and TNF-α. Our findings support the potential beneficial effect of magnesium supplementation on alleviating CAD complications through modulating inflammatory cytokines.
Similar content being viewed by others
Data availability
The data that support the findings of this study are available from the corresponding author, [Ebrahim Eftekhar], upon reasonable request.
References
Abbas AM, Sakr HF (2016) Effect of magnesium sulfate and thyroxine on inflammatory markers in a rat model of hypothyroidism. Can J Physiol Pharmacol 20(94):426–432
Adrian M, Chanut E, Laurant P, Gaume V, Berthelot A (2008) A long-term moderate magnesium-deficient diet aggravates cardiovascular risks associated with aging and increases mortality in rats. J Hypertens 14(26):44–52. https://doi.org/10.1097/HJH.0b013e3282f09f68
Brånén L, Hovgaard L, Nitulescu M, Bengtsson E, Nilsson J, Jovinge S (2004) Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 7(24):2137–2142. https://doi.org/10.1161/01.ATV.0000143933.20616.1b
Bruunsgaard H, Skinhøj P, Pedersen AN, Schroll M, Pedersen BK (2000) Ageing, tumour necrosis factor-alpha (TNF- α ) and atherosclerosis: ageing TNF-a and atherosclerosis. Clin Exp Immunol 19(121):255–260. https://doi.org/10.1046/j.1365-2249.2000.01281.x
Chandrasekar B, Colston JT, de la Rosa SD, Rao PP, Freeman GL (2003) TNF-α and H2O2 induce IL-18 and IL-18Rβ expression in cardiomyocytes via NF-κB activation. Biochem Biophys Res Commun 21(303):1152–1158. https://doi.org/10.1016/S0006-291X(03)00496-0
Chandrasekar B, Mummidi S, Valente AJ, Patel DN, Bailey SR, Freeman GL, Hatano M, Tokuhisa T, Jensen LE (2005) The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-jun N-terminal kinase, and activator protein-1 signaling. J Biol Chem 27(280):26263–26277. https://doi.org/10.1074/jbc.M502586200
Dinarello CA, Novick D, Kim S, Kaplanski G (2013) Interleukin-18 and IL-18 binding protein. Front Immunol 24:4. https://doi.org/10.3389/fimmu.2013.00289
Farshidi H, Sobhani AR, Eslami M, Azarkish F, Eftekhar E, Keshavarz M, Soltani N (2020) Magnesium sulfate administration in moderate coronary artery disease patients improves atherosclerotic risk factors: a double-blind clinical trial study. J Cardiovasc Pharmacol 76:321–328. https://doi.org/10.1097/FJC.0000000000000874
Gao F, Ding B, Zhou L, Gao X, Guo H, Xu H (2013) Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-κB pathway. J Surg Res 37(184):944–950. https://doi.org/10.1016/j.jss.2013.03.034
Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schönbeck U (2002) Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages. J Exp Med 26(195):245–257. https://doi.org/10.1084/jem.20011022
Gisterå A, Hansson GK (2017) The immunology of atherosclerosis. Nat Rev Nephrol 10(13):368–380. https://doi.org/10.1038/nrneph.2017.51
Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 1(12):204–212. https://doi.org/10.1038/ni.2001
Hartman J, Frishman WH (2014) Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev 29(22):147–151. https://doi.org/10.1097/CRD.0000000000000021
Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R (1999) Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32(19):2364–2367. https://doi.org/10.1161/01.ATV.19.10.2364
Joris PJ, Plat J, Bakker SJ, Mensink RP (2016) Long-term magnesium supplementation improves arterial stiffness in overweight and obese adults: results of a randomized, double-blind, placebo-controlled intervention trial. Am J Clin Nutr 103:1260–1266. https://doi.org/10.3945/ajcn.116.131466
Kaptoge S, Seshasai SRK, Gao P, Freitag DF, Butterworth AS, Borglykke A, Di Angelantonio E, Gudnason V, Rumley A, Lowe GDO, Jorgensen T, Danesh J (2014) Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 30(35):578–589. https://doi.org/10.1093/eurheartj/eht367
Karasawa T, Takahashi M (2017) Role of NLRP3 inflammasomes in atherosclerosis. J Atheroscler Thromb 3(24):443–451. https://doi.org/10.5551/jat.RV17001
Kim DJ, Xun P, Liu K, Loria C, Yokota K, Jacobs DR, He K (2010) Magnesium intake in relation to systemic inflammation, insulin resistance, and the incidence of diabetes. Diabetes Care 33(33):2604–2610. https://doi.org/10.2337/dc10-0994
Lei X, Buja LM (1996) Detection and localization of tumor necrosis factor-α in WHHL rabbit arteries. Atherosclerosis 17(125):81–89
Libby P, Ridker PM, Hansson GK (2009) Inflammation in atherosclerosis. J Am Coll Cardiol 16(54):2129–2138. https://doi.org/10.1016/j.jacc.2009.09.009
Lin CY, Tsai PS, Hung YC, Huang CJ (2010) L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate. Br J Anaesth 38(104):44–51. https://doi.org/10.1093/bja/aep336
Lusis AJ (2000) Atherosclerosis. Nature 2(407):233–241. https://doi.org/10.1038/35025203
Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A (2001) Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation 25(104):1598–1603. https://doi.org/10.1161/hc3901.096721
McLean AS, Huang SJ, Salter M (2008) Bench-to-bedside review: the value of cardiac biomarkers in the intensive care patient. Crit Care Lond Engl 6(12):215. https://doi.org/10.1186/cc6880
Moriya J (2019) Critical roles of inflammation in atherosclerosis. J Cardiol 35(73):22–27. https://doi.org/10.1016/j.jjcc.2018.05.010
Muga MA, Chao JC-J (2014) Effects of fish oil and spirulina on oxidative stress and inflammation in hypercholesterolemic hamsters. BMC Complement Altern Med 9(14):470. https://doi.org/10.1186/1472-6882-14-470
Naghipour B, Faridaalaee G, Shadvar K, Bilehjani E, Khabaz A, Fakhari S (2016) Effect of prophylaxis of magnesium sulfate for reduction of postcardiac surgery arrhythmia: randomized clinical trial. Ann Card Anaesth 13(19):662. https://doi.org/10.4103/0971-9784.191577
Ridker PM (2016) From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res 31(118):145–156. https://doi.org/10.1161/CIRCRESAHA.115.306656
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 8(101):1767–1772. https://doi.org/10.1161/01.CIR.101.15.1767
Schutten JC, Joris PJ, Groendijk I, Eelderink C, Groothof D, van der Veen Y, Westerhuis R, Goorman F, Danel RM, de Borst MH, Bakker SJL (2022) Effects of magnesium citrate, magnesium oxide, and magnesium sulfate supplementation on arterial stiffness: a randomized, double-blind, placebo-controlled intervention trial. J. Am. Heart Assoc. 11:e021783. https://doi.org/10.1161/JAHA.121.021783
Shi C-X, Qi Q-H, Xu J, Zhao WW (2020) Protective effect of magnesium sulfate on cranial nerves in preeclampsia rats through NF-κB/ICAM-1 pathway. Eur. Rev. Med. Pharmacol. Sci. 24:2785–2794. https://doi.org/10.26355/eurrev_202003_20639
Song Y, Li TY, van Dam RM, Manson JE, Hu FB (2007) Magnesium intake and plasma concentrations of markers of systemic inflammation and endothelial dysfunction in women. Am J Clin Nutr 34(85):1068–1074. https://doi.org/10.1093/ajcn/85.4.1068
Sugimoto J et al (2012) Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism. J. Immunol. 36(188):6338–6346. https://doi.org/10.4049/jimmunol.1101765
Tangvoraphonkchai K, Davenport A (2018) Magnesium and cardiovascular disease. Magnesium 15(25):251–260. https://doi.org/10.1053/j.ackd.2018.02.010
Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 5(86):515–581. https://doi.org/10.1152/physrev.00024.2005
Tousoulis D, Oikonomou E, Economou EK, Crea F, Kaski JC (2016) Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J 11(37):1723–1732. https://doi.org/10.1093/eurheartj/ehv759
Wood IS, Wang B, Jenkins JR, Trayhurn P (2005) The pro-inflammatory cytokine IL-18 is expressed in human adipose tissue and strongly upregulated by TNFα in human adipocytes. Biochem Biophys Res Commun 23(337):422–429. https://doi.org/10.1016/j.bbrc.2005.09.068
Yang X, Jia J, Yu Z, Duanmu Z, He H, Chen S, Qu C (2020) Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC Cardiovasc Disord 18(20):133. https://doi.org/10.1186/s12872-020-01391-7
Yu X, Guan P-P, Zhu D, Liang Y-Y, Wang T, Wang Z-Y, Wang P (2018) Magnesium ions inhibit the expression of tumor necrosis factor α and the activity of γ-secretase in a β-amyloid protein-dependent mechanism in APP/PS1 transgenic mice. Front Mol Neurosci 21(11):172. https://doi.org/10.3389/fnmol.2018.00172
Zhang LW, Warrington JP (2016) Magnesium sulfate prevents placental ischemia-induced increases in brain water content and cerebrospinal fluid cytokines in pregnant rats. Front Neurosci 28:10. https://doi.org/10.3389/fnins.2016.00561
Zhu D, You J, Zhao N, Xu H (2019) Magnesium regulates endothelial barrier functions through TRPM7, MagT1, and S1P1. Adv Sci 12(6):1901166. https://doi.org/10.1002/advs.201901166
Funding
This work was supported by the [Molecular Medicine Research Center, Hormozgan University of Medical Sciences] under Grant numbers [970325 and 970362].
Author information
Authors and Affiliations
Contributions
EE: contributed to study design, supervised all stages of study and revised the manuscript. FM: methodology experimentation, wrote and modified the manuscript. MH; revised the manuscript and participated in methodology experimentation. SO, MSV, SK: participated in methodology experimentation. HF: participated in study design and data gathering. All authors approved the finally manuscript content.
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest.
Ethical approval
The study protocol was approved by the research ethics committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1397.331).
Consent to participate and publish
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national). Informed consent was obtained from all patients for being included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mohebi, F., Ostadhadi, S., Vaziri, M.s. et al. The effect of magnesium sulfate on gene expression and serum level of inflammatory cytokines in coronary artery disease patients. Inflammopharmacol 31, 2421–2430 (2023). https://doi.org/10.1007/s10787-023-01328-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-023-01328-4