Association of plasma folic acid levels with parameters of glutathione metabolism in hypertensive patients with comorbid diseases

Objective. Hypertension (HTN) is characterized by a high incidence of comorbidity. An individual approach to the management of such patientsrequires new markers for differential diagnosis. The pathophysiology of most comorbidities is closely related to endothelial dysfunction triggered by an imbalance in redox processes.

The aim of this work is to assess the relationship between plasma level of folic acid (FA) and the state of the redox system of erythrocyte glutathione in patients with HTN and concomitant target organ damage in cardiovascular diseases (HTN + CVD), chronic kidney disease (HTN + CKD) and discirculatory encephalopathy (HTN + DE).

Design and methods. We enrolled 93 patients with HTN admitted to the clinics of the Pavlov University, and 30 donors of the reference group. We assessed plasma concentration of folic acid, the content of reduced glutathione (GSH) and the activity of glutathione reductase (GR) in erythrocytes.

Results. In HTN patients with the deficiency of FA, a lower content of GSH and activity of GR in erythrocytes were found compared to the HTN patients without deficiency and the reference group. In the groups HTN + CVD and HTN + DE, the GSH level and GR activity correlated with the plasma concentration of FA and were lower in the subgroups with FA deficiency. In subgroups with normal FA content, these parameters did not differ from the reference indicators.

Conclusions. The parameters of GSH and GR in patients with HTN + CVD and HTN + DE, but not HTN + CKD, can be considered as potential markers of functional FA deficiency.

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. Am J Hypertens. 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(2):211–223. doi:10.2174/1389200024605163

4. Anguera MC, Suh JR, Ghandour H, Nasrallah IM, Selhub J, Stover PJ. Methylenetetrahydrofolate synthetase regulates folate turnover and accumulation. J Biol Chem. 2003;278(32):29856– 29862. doi:10.1074/jbc.M302883200

5. 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

6. Yuyun MF, Ng LL, Ng GA. Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? Microvasc Res. 2018;119:7–12. doi:10.1016/j.mvr.2018.03.012

7. Mikashinowich ZI, Nagornaya GJ, Kovalenko TD. The role of antioxidant enzymes in pathogenesis of arterial hypertension at teenagers. Med Herald South Russ. 2013;(3):60–62. doi:10.21886/2219-8075-2013-3-60-62. In Russian.

8. Montezano AC, 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

9. Montezano AC, Touyz RM. Reactive oxygen species, vascular noxs, and hypertension: focus on translational and clinical research. Antioxid Redox Signal. 2014;20(1):16–182. doi:10.1089/ars.2013.5302

10. Rybka J, Kupczyk D, Kędziora-Kornatowska K, Motyl J, Czuczejko J, Szewczyk-Golec K et al. Glutathionerelated antioxidant defense system in elderly patients treated for hypertension. Cardiovasc Toxicol. 2011;11(1):1–9. doi:10.1007/s12012-010-9096-5

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

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

13. Ogilvie RP, Lutsey PL, Heiss G, Folsom AR, Steffen LM. Dietary intake and peripheral arterial disease incidence in middleaged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2017;105(3):651–659. doi:10.3945/ajcn.116.137497

14. Aleksandrovа LA, Subbotina TF, Zhloba AA. The relationship of folate deficiency, hyperhomocysteinemia and glutathione metabolism in hypertensive patients. Arterial’naya Gipertenziya = Arterial Hypertension. 2020;26(6):656–664. doi:10.18705/1607-419X‑2020-26-6-656-664. In Russian.

15. Alexandrova LA, Mironova JA, Filippova NA, Тrjofimov VI. Glutathione metabolism of erythrocytes in the paroxysmal nocturnal hemoglobinuria. Regionarnoe Krovoobrashchenie i Mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation. 2015;14(4):60–65. doi:10.24884/1682-6655-2015-14-4-60-65. In Russian.

16. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489–492. doi:10.1093/jn/134.3.489

17. Da Silva AP, Marinho C, Gonçalves MC, Monteiro C, Laires MJ, Falcão LM et al. Decreased erythrocyte activity of methemoglobin and glutathione reductases may explain age-related high blood pressure. Rev Port Cardiol. 2010;29(3):403–412.

18. Rao KNS, Shen X, Pardue S, Krzywanski DM. Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II. Redox Biol. 2020;36:101650. doi:10.1016/j.redox.2020.101650

19. Chignalia AZ, Isbatan A, Patel M, Ripper R, Sharlin J, Shosfy J et al. Pressure-dependent NOS activation contributes to endothelial hyperpermeability in a model of acute heart failure. Biosci Rep. 2018;38(6): BSR20181239. doi:10.1042/BSR20181239

20. Hsu CN, Tain YL. Targeting the renin-angiotensinaldosterone system to prevent hypertension and kidney disease of developmental origins. Int J Mol Sci. 2021;22(5):2298. doi:10.3390/ijms22052298

21. Lee H, Kim E. Repositioning medication for cardiovascular and cerebrovascular disease to delay the onset and prevent progression of Alzheimer’s disease. Arch Pharm Res. 2020;43(9):932–960. doi:10.1007/s12272-020-01268-5

22. Wang K, Dong Y, Liu J, Qian L, Wang T, Gao X et al. Effects of REDOX in regulating and treatment of metabolic and inflammatory cardiovascular diseases. Oxid Med Cell Longev. 2020;2020:5860356. doi:10.1155/2020/5860356