Immunomodulatory effects of interval hypoxic therapy and stimulated hypercapnia in hypertensive disease: impact on Hsp70, NF-κB levels, and cytokine profile

In the pathogenesis of hypertension, stress-induced Hsp70 family chaperones and the transcription factor NF-κB, which regulates inflammatory and immune responses, play key roles.

Objective - to assess the effects of normobaric intermittent hypoxic therapy combined with stimulated hypercapnia on immunological parameters in patients with stage I hypertension.

Materials and methods. 160 men aged 35-50 years with stage I hypertension were examined. Serum concentrations of Hsp70, interleukins IL-6, IL-10, TNF-α, and NF-κB levels in blood mononuclear cells were measured by solid-phase ELISA before and after the hypoxic therapy course.

Results. After an 18-day course, patients showed significant decreases in Hsp70 from 3.65±0.24 to 2.95±0.23 ng/mL (p<0.05) and NF-κB from 5.67±0.31 to 4.45±0.36 ng/mL (p<0.05), along with normalization of the cytokine profile: IL-6 and TNF-α decreased from 7.21±0.31 to 6.34±0.22 pg/mL (p<0.05) and from 4.63±0.34 to 3.56±0.27 pg/mL (p<0.05), respectively, while IL-10 increased from 2.41±0.18 to 3.18±0.26 pg/mL (p<0.05). Significant positive correlations were found between IL-6, TNF-α, and blood pressure levels. Oxidative stress was attenuated, with a decrease in malondialdehyde and increased activity of antioxidant enzymes.

Conclusion. In patients with stage I hypertension, the combination of intermittent hypoxic therapy and stimulated hypercapnia reduces Hsp70 and NF-κB, normalizes the cytokine profile, and lowers oxidative stress, confirming its immunomodulatory and anti-inflammatory effects.

1. Kobalava Zh.D., Konradi A.O., Nedogoda S.V., Shlyakhto E.V., Arutyunov G.P., Baranova E.I., Barbarash O.L., Bobkova N.V., et al. 2024 Clinical practice guidelines for Hypertension in adults.Russian Journal of Cardiology. 2024;29(9):6117 (in Russ.). DOI:10.15829/1560-4071-2024-6117. EDN: GUEWLU.

2. Rossi G.P., Bagordo D., Rossi F.B., Pintus G., Rossitto G., Seccia T.M. 'Essential' arterial hypertension: time for a paradigm change. J Hypertens. 2024;42(8):1298-1304. DOI: 10.1097/HJH.0000000000003767.

3. Weinstein S, Leibowitz A. Role of the immune system in the pathogenesis of hypertension. Harefuah. 2021;160(4):256-259.

4. Lazaridis A., Gavriilaki E., Douma S., Gkaliagkousi E. Toll-Like Receptors in the Pathogenesis of Essential Hypertension. A Forthcoming Immune-Driven Theory in Full Effect.Int J Mol Sci. 2021;22(7):3451. DOI: 10.3390/ijms22073451.

5. Jia X.Y., Jiang D.L., Jia X.T., Fu L.Y., Tian H., Liu K.L., Qi J., Kang Y.M., et al. Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus. Phytomedicine. 2023;118:154951. DOI: 10.1016/j.phymed.2023.154951.

6. Gaptulbarova K.A., Tsyganov M.M., Pevzner A.M., Ibragimova M.K., Litviakov N.V. NF-kB as a potential prognostic marker and a candidate for targeted therapy of cancer. Exp Oncol. 2020;42(4):263-269. DOI: 10.32471/exp-oncology.2312-8852.vol-42-no-4.15414.

7. Yu M., Wu X., Wang J., He M., Han H., Hu S., Xu J., Yang M., et al. Paeoniflorin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing TAK1-MAPK/NF-κB pathways.Int J Med Sci. 2022;19(4):681-694. DOI: 10.7150/ijms.69289.

8. Borukaeva I.Kh., Abazova Z.Kh., Shkhagumov K.Yu., Temirzhanova F.Kh., Ashagre S.M., Ragimbayeva M.R. Pathophysiological mechanisms underlying the effectiveness of interval hypoxic therapy and enteral oxygen therapy in the treatment of patients with hypertension.Russian Journal of Cardiology, 2021;26(S6):17 (in Russ.). EDN: YMQSMH.

9. Ignatenko G.A., Bagriy A.E., Ignatenko T.S., Tolstoy V.A., Evtushenko I.S., Mykhailichenko E.S. Possibilities and Prospects of Hypoxytherapy Application in Cardiology. The Russian Archives of Internal Medicine. 2023;13(4):245-252 (in Russ.). DOI: 10.20514/2226-6704-2023-13-4-245-252. EDN: AHXHPL.

10. Velizhanina I.A., Gapon L.I., Evdokimova O.V., Velizhanina E.S., Rudakov A.V. Evaluation of the effectiveness of intermittent normobaric hypoxic therapy in the treatment of arterial hypertension based on 24-hour ambulatory blood pressure monitoring. Clinical Practice. 2017;(4):51-55. (in Russ.). EDN: YWSVWL

11. Borukaeva I.Kh., Abazova Z.Kh., Ivanov A.B., Misirova I.A., Shkhagumov K.Yu., Shavaeva F.V., Mоlov A.A., Kipkeeva T.B., Shokueva A.G. Preservation of the immunomodulatory effect of interval hypoxytherapy after coronavirus infection in the long-term period. Medical Immunology. 2023;25(4):809-814 (in Russ.). DOI: 10.15789/1563-0625-POT-2767. EDN: YFNCZG.

12. Shishkina O.S. Buteiko breathing exercises & Its effect on human body.International scientific journal "BULLETIN OF SCIENCE". 2022;11(56):161-163 (in Russ.)

13. Salimova S.S., Berkinbay A.B., Kozhakhan S.S., Abdikaim D.G., Abdilakhat U.T., Dzhazykpayeva E.T., Serikzhan F.S., Yergeshbay B.K., et al. The effectiveness of Buteyko breathing training in patients with chronic obstructive pulmonary disease. Phthisiopulmonology. 2025;1(47):151-161 (in Russ.). DOI: 10.26212/2227-1937.2025.56.29.018. EDN: GDHGSV.

14. Kosarev M.O., Sadova V.A., Sumnaya D.B., Nikolaeva I.V. Hypercapnic-hypoxic training with the aid respiratory simulator "CARBONIC" in patients with chronic ischemia of the brain of atherosclerotic genesis. German International Journal of Modern Science. 2021;9:21-25 (in Russ.). DOI: 10.24412/2701-8369-2021-9-1-21-25. EDN: ZBZZJK.

15. Tregub P.P. The Effect of Hypercapnia and Hypoxia on the Physiology and Metabolism of the Cerebral Endothelium in Ischemic Conditions. I.M. Sechenov Russian Journal of Physiology. 2022;108(5):579-593. DOI: 10.31857/S0869813922050120. EDN: TDITXD.

16. Chen Y., Wang K., Di J., Guan C., Wang S., Li Q., Qu Y. Mutation of the BAG-1 domain decreases its protective effect against hypoxia/reoxygenation by regulating HSP70 and the PI3K/AKT signalling pathway in SY-SH5Y cells. Brain Res. 2021;1751:147192. DOI: 10.1016/j.brainres.2020.147192.

17. Madaeva I.M., Kurashova N.A., Semenova N.V., Ukhinov E.B., Kolesnikov S.I., Kolesnikova L.I. Heat Shock Protein HSP70 in Oxidative Stress in Apnea Patients. Bull Exp Biol Med. 2020;169(5):695-697. DOI: 10.1007/s10517-020-04957-9.

18. Shobatake R., Ota H., Takahashi N., Ueno S., Sugie K., Takasawa S. The Impact of Intermittent Hypoxia on Metabolism and Cognition.Int. J. Mol. Sci. 2022;23,12957. DOI: 10.3390/ijms232112957.

19. Liu J.R., Liu Q., Khoury J., Li Y.J., Han X.H., Li J., Ibla J.C. Hypoxic preconditioning decreases nuclear factor κB activity via Disrupted in Schizophrenia-1.Int J Biochem Cell Biol. 2016;70:140-148. DOI: 10.1016/j.biocel.2015.11.013.

20. Korbecki J., Simińska D., Gąssowska-Dobrowolska M., Listos J., Gutowska I., Chlubek D., Baranowska-Bosiacka I. Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.Int J Mol Sci. 2021;22(19):10701. DOI: 10.3390/ijms221910701.

21. Zheng Y., Li Y., Ran X., Wang D., Zheng X., Zhang M., Yu B., Sun Y., et al. Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway. Cell Mol Life Sci. 2022;79(6):311. DOI: 10.1007/s00018-022-04331-0.

22. Schumertl T., Lokau J., Garbers C. IL-6 Signaling in Immunopathology: From Basic Biology to Selective Therapeutic Intervention. Immunotargets Ther. 2025;14:681-695. DOI: 10.2147/ITT.S485684.

23. Zhou L., Zhang H., Liu L., Zhang F., Wang L., Zheng P., Mao Z., Zhu X., et al.Intermittent hypoxia aggravates asthma inflammation via NLRP3/IL-1β-dependent pyroptosis mediated by HIF-1α signalling pathway. Chin Med J (Engl). 2025;138(14):1714-1729. DOI: 10.1097/CM9.0000000000003608.

24. Mishra B., Mishra B., Bachu M., Yuan R., Wingert C., Chaudhary V., Brauner C., Bell R., et al. IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms. Nat Immunol. 2025 May;26(5):748-759. DOI: 10.1038/s41590-025-02137-3.

25. Sato T., Takeda N. The roles of HIF-1α signaling in cardiovascular diseases. J Cardiol. 2023;81(2):202-208. DOI: 10.1016/j.jjcc.2022.09.002.

26. Titova O.N., Kuzubova N.A., Lebedeva E.S. The role of the hypoxia signaling pathway in cellular adaptation to hypoxia.Russian Medical Inquiry. 2020;4(4):207-213 (in Russ.). DOI: 10.32364/2587-6821-2020-4-4-207-213. EDN: EQPBIM.

27. Baly`kin M.V., Sagidova S.A., Zharkov A.S., Ajzyatulova E.D., Pavlov D.A., Antipov I.V. The effect of intermittent hypobaric hypoxia on HIF-1Α expression and morphofunctional changes in the myocardium. Ul`yanovskij mediko-biologicheskij zhurnal. 2017;2:125-135 (in Russ.). DOI: 10.23648/UMBJ.2017.26.6227. EDN: YTFJCP.

28. Hajam Y.A., Rani R., Ganie S.Y., Sheikh T.A., Javaid D., Qadri S.S., Pramodh S., Alsulimani A., et al. Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells. 2022;11(3):552. DOI: 10.3390/cells11030552.

29. Xu X., Pang Y., Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025;10(1):190. DOI: 10.1038/s41392-025-02253-4.

30. Sharma S., Sharma P., Subedi U., Bhattarai S., Miller C., Manikandan S., Batinic-Haberle I., Spasojevic I., et al. Mn(III) Porphyrin, MnTnBuOE-2-PyP5+, Commonly Known as a Mimic of Superoxide Dismutase Enzyme, Protects Cardiomyocytes from Hypoxia/Reoxygenation Induced Injury via Reducing Oxidative Stress.Int J Mol Sci. 2023;24(7):6159. DOI: 10.3390/ijms24076159.