The relationship of folate deficiency, hyperhomocysteinemia and glutathione metabolism in hypertensive patients

Hypertension (HTN) is often accompanied by folic acid (FA) deficiency and hyperhomocysteinemia (HHcy). Reduced glutathione (GSH) and dependent enzymes determine the state of cellular antioxidant and redox systems in cardiovascular pathology.
The aim of our work is to assess the relationship between the status of FA and the presence of HHcy with enzymes of glutathione metabolism and the redox state of erythrocyte glutathione in HTN.
Design and methods. In blood plasma samples from 43 HTN patients admitted to the clinic of Pavlov University, the concentration of FA and total homocysteine (oHcy) was determined. We also evaluated the level of GSH, the activity of glutathione peroxidase and glutathione reductase (GR) in erythrocytes.
Results. In the whole group, GR activity positively correlated with the concentration of FA (R = 0,415; p = 0,001). A significant decrease in GR activity (U/g Hb) was found in the subgroup with the low level of FA [0,8 (0,5–1,1)] compared with the subgroup without a FA deficiency [1,2 (0,9–2,0)]. The GSH level (μM/g Hb) was also lower (p < 0,018) in the subgroup with FA deficiency [1,3 (0,9–2,1)] compared with the subgroup with normal FA levels [1,8 (1,5–4,6)]. A significant decrease in the level of GSH and GR activity in the subgroup with HHcy was found compared with the corresponding parameters in the subgroup without HHcy. However, even in the absence of HHcy patients with FA deficiency demonstrated a significant decrease in GR activity compared to patients without FA deficiency. In this case, GR positively correlated with FA (R = 0,564; p = 0,03).
Conclusions. The deficiency of FA can increase the deficiency of GR activity, regardless of the level of oHcy. The indicator of GR activity in erythrocytes can be considered as a possible marker of functional deficiency of FA in the absence of HHcy.

1. Pravenec M, Kozich V, Krijt J, Sokolová J, Zídek V, Landa V et al. Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure, and Insulin resistance in Spontaneously Hypertensive Rats. American Journal of Hypertension. 2013;26(1):135-140. doi:10.1093/ajh/hps015.

2. Yi X, Zhou Y, Jiang D, Li X, Guo Y, Jiang X. Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Exp Ther Med. 2014;7(5):1100–1110. doi:10.3892/etm.2014.1553.

3. Stanger O. Physiology of folic acid in health and disease. Curr Drug Metab. 2002;3:211–223. doi:10.2174/1389200024605163.

4. Anguera MC, Suh JR, Ghandour H, Nasrallah IM, Selhub J and Stover PJ. Methylenetetrahydrofolate synthetase regulates folate turnover and accumulation. J Biol Chem. 2003;278:29856–29862 doi:10.1074/jbc.M302883200.

5. Poltavtseva OV, Nesterov UI, Teplyakov A T.Homocysteinemia in patients with arterial hypertension and cerebrovascular complications. Sibirskiy meditsinskiy jurnal. 2012;27(4):37-41. (In Russian).

6. Zhloba AA, Subbotina TF. The evaluation of folate status using total homocysteine in hypertensive patients. Medical Journal of the Russian Federation 2019. 25(3):158-165. (In Russian).

7. Zhloba A.A. Laboratory diagnosis of hyperhomocysteinemia. Clinical laboratory consillium. 2009; 26(1): 49-60. (In Russian).

8. Essouma M, Noubiap JN. Therapeutic potential of folic acid supplementation for cardiovascular disease prevention through homocysteine lowering and blockade in rheumatoid arthritis patients Biomarker Research. 2015;3:24. doi 10.1186/s40364-015-0049-9.

9. Shen M, Tan H, Zhou S, Retnakaran R, Smith GN, Davidge ST et al. Serum Folate Shows an Inverse Association with Blood Pressure in a Cohort of Chinese Women of Childbearing Age: A Cross-Sectional Study. PLoS One. 2016;11(5):e0155801. doi:10.1371/journal.pone.0155801.

10. Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2002;22(1):6-13. doi:10.1161/hq0102.102190.

11. Wang Y, Jin Y, Wang Y, Li L, Liao Y, Zhang Y, Yu D. The effect of folic acid in patients with cardiovascular disease: A systematic review and meta-analysis. Medicine(Baltimore).2019;98(37):e17095.doi:10.1097/MD.000000000001709512.

12. Bunout D, Petermann M, Hirsch S, de la Maza P, Suazo M, Barrera G, Kauffman R. Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition 2000;16:434–438. https://doi.org/10.1016/S0899-9007(00)00289-6.

13. Stanhewicz AE, Kenney WL. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev. 2017;75(1):61–70. doi:10.1093/nutrit/nuw053.

14. Stroes ES, van Faassen EE, Yo M, Martasek P, Govers R, Rabelink TJ. Folic acid recerts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86:1129–1134. doi:10.1161/01.res.86.11.1129

15. Mikashinowich ZI, Nagornaya GJ, Kovalenko TD. The role of antioxidant enzymes in pathogenesis of arterial hypertension at teenagers. Medical Herald of the South of Russia. 2013;(3):60-62. (In Russian) https://doi.org/10.21886/2219-8075-2013-3-60-62].

16. Montezano AC and Touyz RM. Molecular mechanisms of hypertension—reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol. 2012;28(3):288–295. doi:10.1016/j.cjca.2012.01.017.

17. Montezano AC and Touyz RM. Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research. Antioxidants and redox signaling. 2014;20(1):164-82. doi:10.1089/ars.2013.5302. Epub 2013 Jun 6.

18. Rybka J, Kupczyk D, Kędziora-Kornatowska K, Motyl J, Czuczejko J, Szewczyk-Golec K et al. Glutathione-Related Antioxidant Defense System in Elderly Patients Treated for Hypertension. Cardiovasc Toxicol. 2011;11(1):1–9. doi:10.1007/s12012-010-9096-5.

19. Ballatori N, Krance SM, Notenboom SN. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191–214. doi:10.1515/BC.2009.033.

20. Alexandrova LA, Mironova JA, Filippova NA, Тrjofimov VI. Glutathione metabolism of erythrocytes in the paroxysmal nocturnal hemoglobinuria. Regional blood circulation and microcirculation. 2015;14(4):60–65. (In Russian.). https://doi.org/10.24884/1682-6655-2015-14-4-60-65.

21. Zhloba A.A., Subbotina T.F. Homocysteinylation score of high molecular weight plasma proteins. Amino Acids. 2014;46(4):893-899. doi:10.1007/s00726-013-1652-4.

22. Chaves FJ, Mansego ML, Blesa S, Gonzalez-Albert V, Jimenez J, Tormos MC. et al. Inadequate cytoplasmic antioxidant enzymes response contributes to the oxidative stress in human hypertension. American Journal of Hypertension. 2007;20:62–69. doi: 10.1016/j.amjhyper.2006.06.006.

23. Silva AP, Marinho C, Goncalves MC, Monteiro C, Laires MJ, Falcao LM et al. Decreased erythrocyte activity of methemoglobin and glutathione reductases may explain age-related high blood pressure. Revista Portuguesa de Cardiologia. 2010;29:403–412.

24. Grossman E. Does Increased Oxidative Stress Cause Hypertension? Diabetes Care. 2008;31(Supplement 2):185-189. doi:10.2337/dc08-s246

25. Durand P, Prost M, Blache D. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis. 1996;121:231-243. doi:10.1016/0021-9150(95)06724-8.

26. Tsai JC, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R et al. Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Proceedings of the National Academy of Sciences. 1994;91:6369–6373. doi:10.1073/pnas.91.14.6369.

27. Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the trassulfuration pathway and its regulation by redox changes. Biochemistry. 2000;39:13005–13011. doi:10.1021/bi001088w.

28. Chen N, Liu Y, Greiner CD, Holtzman JL Physiologic concentrations of homocysteine inhibit the human plasma GSH peroxidase that reduces organic hydroperoxides. J Lab Clin Med. 2000;136:58–65. doi:10.1067/mlc.2000.107692.

29. Handy DE, Zhang Y, Loscalzo J Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J Biol Chem. 2005;280:15518–15525. doi:10.1074/jbc.M501452200.

30. Caruso R, Campolo J, Sedda V, De Chiara B, Dellanoce C, Baudo F. et al. Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia. J Cardiovasc Pharmacol. 2006;47:549–555. doi: 10.1097/01.fjc.0000211748.16573.31.

31. Shaw S, Jayatilleke E, Herbert V, Colman N (1989) Cleavage of folates during ethanol metabolism. Biochem J. 1989;257:277–280. doi:10.1042/bj2570277.

32. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489–92. DOI:10.1093/jn/134.3.489.

33. Brain KL, Allison BJ, Niu Y, Cross CM, Itani N, Kane AD et al. Intervention against hypertension in the next generation programmed by developmental hypoxia. PLOS Biology. 2019;17(1):e2006552. https://doi.org/10.1371/journal.pbio.2006552

34. Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Antihypertensive drugs and reversing of endothelial dysfunction in hypertension. Current Science 2000;2(1):64–70 doi:10.1007/s11906-000-0061-8.

35. Niedzwiecki MM, Hall MN, Liu X, Oka J, Harper KN, Slavkovich V et al. Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults. Epigenetics. 2013;8(7):730–738. doi:10.4161/epi.25012.

36. Mahajan AS, Babbar R, Kansal N, Agarwal SK, Ray PC (2007). Antihypertensive and Antioxidant Action of Amlodipine and Vitamin C in Patients of Essential Hypertension. Journal of clinical biochemistry and nutrition. 2007;40:141-147. doi:10.3164/jcbn.40.141.

37. Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial. JAMA. 2015;313(13):1325–1335. doi:10.1001/jama.2015.2274.