FOXP3, IL2R, CD8A and RORγ gene expression in peripheral blood leukocytes of healthy people and patients with arterial hypertension
https://doi.org/10.15789/1563-0625-FIC-2385
Abstract
Impaired balance of T regulatory and T effector lymphocytes has recently been considered as an important pathogenetic link in arterial hypertension (AH). There are, however, contradictory literature data about contents of these cells in the patients with hypertension, or obtained in experimental animal models of induced hypertension. Most results about changed patterns of immune cells in cardiovascular diseases were obtained by means of flow cytometry. There are also some works on expression of genes encoding surface and cytoplasmic differentiation antigens of immune cells in the patients with cardiovascular pathologies. These results coincide with the data obtained with flow cytometric techniques. Purpose of the present study was to analyze of the levels of gene transcripts encoding differentiation markers of regulatory (FOXP3, IL2R) T cells, effector T subpopulations (T helpers 17 (RORγ), and CD8 lymphocytes (CD8A) in healthy subjects and the patients with arterial hypertension (stages I-II). We examined healthy individuals (40 people, 20 men and 20 women), 27 patients with hypertension who did not receive antihypertensive therapy (14 men and 13 women), 26 hypertensive patients taking β-adrenergic receptor blockers (metoprolol or bisoprolol), including 12 men and 14 women. The relative levels of transcripts in peripheral blood leukocytes were assessed by real-time RT-PCR. It was shown that the transcriptional activity of FOXP3, IL2R, RORγ, and CD8A genes in peripheral blood leukocytes of the diseased people was significantly higher than in healthy individuals (p < 0.01). This finding may indicate an increased number of circulating T regulatory lymphocytes, CD8+ cells and T helpers 17 in hypertensive patients, and activation of T cell immunity in these patients. There were no statistically significant gender differences in FOXP3, IL2R, RORγ and CD8A gene expression in leukocytes, both in the group of healthy people and in hypertensive patients. The patients receiving cardioselective β-adrenergic receptor blockers (metoprolol and bisoprolol) exhibited lower expression of these genes, thus, probably, indicating antiinflammatory and immunomodulatory properties of these drugs.
About the Authors
L. V. TopchievaRussian Federation
Topchieva Ludmila V., PhD (Biology), Leading Research Associate, Laboratory of Genetics
185910, Republic of Karelia, Petrozavodsk, Pushkinskaya str., 11
V. A. Korneva
Russian Federation
Korneva Viktoria A., PhD (Medicine), Associate Professor, Department of Faculty Therapy, Phthisiology, Infectious Diseases and Epidemiology, Medical Institute
Republic of Karelia, Petrozavodsk
I. E. Malysheva
Russian Federation
Malysheva Irina E., PhD (Biology), Senior Research Associate, Laboratory of Genetics
Republic of Karelia, Petrozavodsk
References
1. Trushina E.N., Mustafina O.K., Jorge S.S., Bogdanov A.R., Sentsova T.B., Zaletova E.S., Kuznetsov V.D. The cell immunity in patients with arterial hypertension and obesity. Voprosy pitaniya = Problems of Nutrition, 2012, no. 6, pp. 19-26. (In Russ.)
2. Freidlin I.S. Regulatory T-cells: origin and function. Meditsinskaya immunologiya = Medical Immunology (Russia), 2005, Vol. 7, no. 4, pp. 347-354. (In Russ.) doi: 10.15789/1563-0625-2005-4-347-354.
3. Agabiti-Rosei C., Trapletti V., Piantoni S., Airò P., Tincani A., de Ciuceis C., Rossini C., Mittempergher F., Titi A., Portolani N., Caletti S., Coschignano M.A., Porteri E., Tiberio G.A.M., Pileri P., Solaini L., Kumar R., Ministrini S., Agabiti Rosei E., Rizzoni D. Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery. PLoS One, 2018, Vol. 13, no. 5, 0197178. doi: 10.1371/journal.pone.0197178.
4. Ba D., Takeichi N., Kodama T., Kobayashi H. Restoration of T cell depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts. J. Immunol., 1982, Vol. 128, no. 3, pp. 1211-1216.
5. Barhoumi T., Kasal D.A., Li M.W., Shbat L., Laurant P., Neves M.F., Paradis P., Schiffrin E.L. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension, 2011, Vol. 57, no. 3, pp. 469-476.
6. Belanger K.M., Crislip G.R., Gillis E.E., Abdelbary M., Musall J.B., Mohamed R., Baban B., Elmarakby A., Brands M.W., Sullivan J.C. Greater T regulatory cells in females attenuate DOCA-salt induced increases in blood pressure versus males. Hypertension, 2020, Vol. 75, no. 6, pp. 1615-1623.
7. Caillon A., Paradis P., Schiffrin E.L. Role of immune cells in hypertension. Br. J. Pharmacol., 2019, Vol. 176, no. 12, pp. 1818-1828.
8. Chiasson V.L., Talreja D., Young K.J., Chatterjee P., Banes-Berceli A.K., Mitchell B.M. FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension. Hypertension, 2011, Vol. 57, no. 6, pp. 1167-1175.
9. Crislip G.R., Sullivan J.C. T-cell involvement in sex differences in blood pressure control. Clin. Sci. (Lond.), 2016, Vol. 130, no. 10, pp. 773-783.
10. Crowley S.D., Song Y.S., Lin E.E., Griffiths R., Kim H.S., Ruiz P. Lymphocyte responses exacerbate angiotensin II-dependent hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2010, Vol. 298, no. 4, pp. R1089-R1097.
11. de Ciuceis C., Rossini C., Airò P., Scarsi M., Tincani A., Tiberio G.A.M., Piantoni S., Porteri E., Solaini L., Duse S., Semeraro F., Petroboni B., Mori L., Castellano M., Gavazzi A., Agabiti Rosei C., Agabiti Rosei E., Rizzoni D. Relationship between different subpopulations of circulating CD4+ T-lymphocytes and microvascular structural alterations in humans. Am. J. Hypertens., 2017, Vol. 30, no. 1, pp. 51-60.
12. Gackowska L., Michałkiewicz J., Helmin-Basa A., Kłosowski M., Niemirska A., Obrycki Ł., Kubiszewska I., Wierzbicka A., Litwin M. Regulatory T-cell subset distribution in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage. J. Hypertens., 2020, Vol. 38, no. 4, pp. 692-700.
13. Gackowska L., Michałkiewicz J., Niemirska A., Helmin-Basa A., Kłosowski M., Kubiszewska I., Obrycki Ł., Szalecki M., Wierzbicka A., Kułaga Z., Wiese M., Litwin M. Loss of CD31 receptor in CD4+ and CD8+ T-cell subsets in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage J. Hypertens., 2018, Vol. 36, no. 11, pp. 2148-2156.
14. Harrison D.G., Guzik T.J., Lob H.E., Madhur M.S., Marvar P.J., Thabet S.R., Vinh A., Weyand C.M. Inflammation, Immunity and Hypertension. Hypertension, 2011, Vol. 57, no. 2, pp. 132-140.
15. Huang H., Lu Z., Jiang C., Liu J., Wang Y., Xu Z. Imbalance between Th17 and regulatory T-cells in sarcoidosis. Int. J. Mol. Sci., 2013, Vol. 14, no. 11, pp. 21463-21473.
16. Itani H.A., McMaster W.G. Jr., Saleh M.A., Nazarewicz R.R., Mikolajczyk T.P., Kaszuba A.M., Konior A., Prejbisz A., Januszewicz A., Norlander A.E., Chen W., Bonami R.H., Marshall A.F., Poffenberger G., Weyand C.M., Madhur M.S., Moore D.J., Harrison D.G., Guzik T.J. Activation of human T cells in hypertension: studies of humanized mice and hypertensive humans. Hypertension, 2016, Vol. 68, no. 1, pp. 123-132.
17. Ji Q., Cheng G., Ma N., Huang Y., Lin Y., Zhou Q., Que B., Dong J., Zhou Y., Nie S. Circulating Th1, Th2, and Th17 levels in hypertensive patients. Dis. Markers, 2017, Vol. 2017, 7146290. doi: 10.1155/2017/7146290.
18. Katsuki M., Hirooka Y., Kishi T., Sunagawa K. Decreased proportion of Foxp3+ CD4+ regulatory T cells contributes to the development of hypertension in genetically hypertensive rats. J. Hypertens., 2015, Vol. 33, no. 4, pp. 773-783.
19. Khan M.M., Sansoni P., Silverman E.D., Engleman E.G., Melmon K.L. Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes. Biochem. Pharmacol., 1986, Vol. 35, no. 7, pp. 1137-1142.
20. Kim C.H. FOXP3 and its role in the immune system. Adv. Exp. Med. Biol., 2009, Vol. 665, pp. 17-29.
21. Kim J.Y., Eunjo L., Koo S., Kim C.-W., Kim I. Transfer of Th17 from adult spontaneous hypertensive rats accelerates development of hypertension in juvenile spontaneous hypertensive rats. Biomed Res. Int., 2021, 6633825. doi: 10.1155/2021/6633825.
22. Kohm A.P., Sanders V.M. Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol. Rev., 2001, Vol. 53, no. 4, pp. 487-525.
23. Koushki K., Shahbaz S. K., Mashayekhi K., MahvashSadeghi M., Zayeri Z.D., Taba M.Y., Banach M., AlRasadi K., Johnston T.P., Amirhossein Sahebkar A. Anti-inflammatory action of statins in cardiovascular disease: the role of inflammasome and toll-like receptor pathways. Clin. Rev. Allergy Immun., 2020, Vol. 60, no. 2, pp. 175-199.
24. Lee E., Kim N., Kang J., Yoon S., Lee H.A., Jung H., Kim S.H., Kim I. Activated pathogenic Th17 lymphocytes induce hypertension following high-fructose intake in Dahl salt-sensitive but not Dahl salt-resistant rats. Dis. Model. Mech., 2020, Vol. 13, no. 5, dmm044107. doi: 10.1242/dmm.044107.
25. Li Q., Wang Y., Chen K., Zhou Q., Wei W., Wang Y. The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronare syndrome. Biochem. Bioph. Res. Comm., 2010, Vol. 394, no. 3, pp. 836-842.
26. Liu Z., Zhao Y., Wei F., Ye L., Lu F., Zhang H., Diao Y., Song H., Qi Z. Treatment with telmisartan/ rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. Atherosclerosis, 2014, Vol. 233, no. 291, e299. doi: 10.1016/j.atherosclerosis.2013.12.004.
27. Marino F., Cosentino M. Adrenergic modulation of immune cells: an update. Amino Acids, 2013, Vol. 45, no. 1, pp. 55-71.
28. Mikolajczyk T.P., Guzik T.J. Adaptive immunity in hypertension. Curr. Hypertens. Rep., 2019, Vol. 21, no. 9, 68. doi: 10.1007/s11906-019-0971-6.
29. Ni X., Wang A., Zhang L., Shan L.-Y., Zhang H.-C., Li L., Si J.-Q., Luo J., Li X.-Z., Ma K.-T. Up-regulation of gap junction in peripheral blood T lymphocytes contributes to the inflammatory response in essential hypertension. PLoS One, 2017, Vol. 12, no. 9, e0184773. doi: 10.1371/journal.pone.0184773.
30. Pinto J.P., Dias V., Zoller H., Porto G., Carmo H., Carvalho F., de Sousa M. Hepcidin messenger RNA expression in human lymphocytes. Immunology, 2010, Vol. 130, no. 2, pp. 217-230.
31. Rai A., Narisawa M., Li P., Pia L., li Y., Yang G., Cheng X.W. Adaptive immune disorders in hypertension and heart failure: focusing on T-cell subset activation and clinical implications. J. Hypertens., 2020, Vol. 38, no. 10, pp. 1878-1889.
32. Renaudin C., Bataillard A., Sassard J. Partial transfer of genetic hypertension by lymphoid cells in Lyon rats. J. Hypertens., 1995, Vol. 13, no. 12, Pt 2, pp. 1589-1592.
33. Saxena A., Dobaczewski M., Rai V., Haque Z., Chen W., Li N., Frangogiannis N.G. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am. J. Physiol. Heart Circ. Physiol., 2014, Vol. 307, no. 8, pp. H1233-H1242.
34. Sereti E., Stamatelopoulos K.S., Zakopoulos N.A., Evangelopoulou A., Mavragani C.P., Evangelopoulos M.E. Hypertension: an immune related disorder? Clin. Immunol., 2019, Vol. 212, 108247. doi: 10.1016/j.clim.2019.108247.
35. Tesmer L.A., Lundy S.K., Sarkar S., Fox D.A. Th17 cells in human disease. Immunol. Rev., 2008, Vol. 223, pp. 87-113.
36. Tipton A.J., Baban B., Sullivan J.C. Female spontaneously hypertensive rats have greater renal antiinflammatory T lymphocyte infiltration than males. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2012, Vol. 303, no. 4, pp. 359-367.
37. Trott D.W., Thabet S.R., Kirabo A., Saleh M.A., Itani H., Norlander A.E., Wu J., Goldstein A., Arendshorst W.J., Madhur M.S., Chen W., Li C.I., Shyr Y., Harrison D.G. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension, 2014, Vol. 64, no. 5, pp. 1108-1115.
38. Wenzel U., Turner J.E., Krebs C., Kurts C., Harrison D.G., Ehmke H. Immune mechanisms in arterial hypertension. J. Am. Nephrol., 2016, Vol. 27, no. 3, pp. 677-686.
39. Williams B., Mancia G., Spiering W., Agabiti Rosei T., Azizi M., Burnier M., Clement D.L., Coca A., de Simone G., Dominiczak A., Kahan T., Mahfoud F., Redon J., Ruilope L., Zanchetti A., Kerins M., Kjeldsen S.E., Kreutz R., Laurent S., Lip G.Y.H., McManus R., Narkiewicz K., Ruschitzka F., Schmieder R.E., Shlyakhto E., Tsioufis C.,Aboyans V., Desormais I. Practice Guidelines for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. Blood Press., 2018, Vol. 27, no. 6, pp. 314-340.
40. Xu L., Chen G., Liang Y., Zhou C., Zhang F., Fan T., Chen X., Zhou H., Yuan W. T helper 17 cell responses induce cardiac hypertrophy and remodeling in essential hypertension. Pol. Arch. Intern. Med., 2021, Vol. 131, no. 3, pp. 257-265.
41. Youn J.-C., Yu H.T., Lim B.J., Koh M.J., Lee J., Chang D.-Y., Choi Y.S., Lee S.-H., Kang S.-M., Jang Y., Yoo O.J., Shin E.-C., Park S. Immunosenescent CD8+ T Cells and C-X-C chemokine receptor Type 3 chemokines are increased in human hypertension. Hypertension, 2013, Vol. 62, no. 1, pp. 126-133.
42. Zhu R., Chen L., Xiong Y., Wang N., Xie X., Hong Y., Meng Z. An upregulation of CD8+CD25+Foxp3+ cells with suppressive function through interleukin 2 pathway in pulmonary arterial hypertension. Exp. Cell Res., 2017, Vol. 358, no. 2, pp. 182-187.
Supplementary files
Review
For citations:
Topchieva L.V., Korneva V.A., Malysheva I.E. FOXP3, IL2R, CD8A and RORγ gene expression in peripheral blood leukocytes of healthy people and patients with arterial hypertension. Medical Immunology (Russia). 2022;24(2):273-282. (In Russ.) https://doi.org/10.15789/1563-0625-FIC-2385