Гены, представляющие стресс-зависимую компоненту при развитии артериальной гипертонии

Гипертония считается ведущим фактором риска развития многих сердечно-сосудистых заболеваний. Одним из ключевых факторов, способствующих развитию гипертонии, является хронический психоэмоциональный стресс. Изучение молекулярно-генетических механизмов развития гипертонии человека проводят на животных, в том числе на специально созданных инбредных линиях крыс, моделирующих различные формы гипертонии чело века. В настоящей работе использованы данные из базы данных RatDEGdb о 144 генах гипоталамуса, которые представляют общий ответ на рестрикционный стресс у гипертензивных крыс НИСАГ и нормотензивных крыс WAG. Эти гены крыс были аннотированы изменениями экспрессии ортологичных им генов человека с использованием данных о 17 458 дифференциально экспрессирующихся генах (ДЭГ) пациентов с артериальной гипертензией по сравнению с нормотензивными пациентами. Для выявленных пар ортологов между ДЭГ гипоталамуса крысы после рестрикцион ного стресса и пациентов с артериальной гипертензией применили анализ главных компонент. Две главные компо ненты, соответствующие линейной комбинации значений log2 изменений экспрессии, связанные со сходством (PC1) и различием (PC2) ответа на психоэмоциональный стресс двух линий крыс, с одной стороны, и разными формами гипертонии человека, с другой, объясняли соответственно 64 и 33 % дисперсии дифференциальной экспрессии генов. Выявленная значимая корреляция между значениями PC1 и PC2 для группы ДЭГ со стресс-индуцированным снижением экспрессии указывает на существование общего молекулярного механизма между психоэмоциональ ным стрессом и гипертонией. Их функциональная аннотация позволила предположить, что стресс-индуцированное снижение экспрессии генов, участвующих в функционировании плазматической мембраны и одновременно во взаи модействии с межклеточным пространством, является наиболее вероятным вкладом психоэмоционального стресса в формирование гипертензивного статуса пациентов, а транскрипционный фактор SMARCA4 – наиболее вероятным участником эпигенетической модификации экспрессии генов в результате хронического стресса. Также предложены маркеры периферической крови для диагностики психоэмоционального стресса.

1. Advani V.M., Ivanov P. Translational control under stress: reshaping the translatome. BioEssays. 2019;41(5):e1900009. doi 10.1002/bies.201900009

2. Ahn S., Jeong E., Min J.W., Kim E., Choi S.S., Kim C.J., Lee D.C. Identification of genes dysregulated by elevation of microRNA-210levels in human trophoblasts cell line, Swan 71. Am J Reprod Immunol. 2017;78(5):e12722. doi 10.1111/aji.12722

3. Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010. Available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/

4. Awad K.S., Elinoff J.M., Wang S., Gairhe S., Ferreyra G.A., Cai R., Sun J., Solomon M.A., Danner R.L. Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery

5. endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2016;310(2): L187-L201. doi 10.1152/ajplung.00303.2015

6. Bali A., Gupta S., Singh N., Jaggi A.S. Implicating the role of plasma membrane localized calcium channels and exchangers in stress-induced deleterious effects. Eur J Pharmacol. 2013;714(1-3):229-238. doi 10.1016/j.ejphar.2013.06.010

7. Bautista L.E., Bajwa P.K., Shafer M.M., Malecki K.M.C., McWilliams C.A., Palloni A. The relationship between chronic stress, hair cortisol and hypertension. Int J Cardiol Hypertens. 2019;2:100012.

8. doi 10.1016/j.ijchy.2019.100012

9. Baymiller M., Moon S.L. Stress granules as causes and consequences of translation suppression. Antioxid Redox Signal. 2023;39(4-6): 390-409. doi 10.1089/ars.2022.0164

10. Bikulciene I., Baleisis J., Mazgelyte E., Rudys R., Vosyliute R., Simkunaite-Rizgeliene R., Kaminskas A., Karciauskaite D. Impact of chronic psychological stress on platelet membrane fatty acid composition in a rat model of type 1 diabetes Mellitus. Lipids Health Dis. 2024;23(1):69. doi 10.1186/s12944-024-02067-3

11. Burford N.G., Webster N.A., Cruz-Topete D. Hypothalamic-pituitaryadrenal axis modulation of glucocorticoids in the cardiovascular system. Int J Mol Sci. 2017;18(10):2150. doi 10.3390/ijms18102150

12. Burnstein K.L., Bellingham D.L., Jewell C.M., Powell-Oliver F.E., Cidlowski J.A. Autoregulation of glucocorticoid receptor gene expression. Steroids. 1991;56(2):52-58. doi 10.1016/0039-128x(91)90124-e

13. Carmichael C.Y., Wainford R.D. Hypothalamic signaling mechanisms in hypertension. Curr Hypertens Rep. 2015;17(5):39. doi 10.1007/s11906-015-0550-4

14. Chadaeva I., Ponomarenko P., Kozhemyakina R., Suslov V., Bogomolov A., Klimova N., Shikhevich S., Savinkova L., Oshchepkov D., Kolchanov N.A., Markel A., Ponomarenko M. Domestication explains two-thirds of differential-gene-expression variance between domestic and wild animals; the remaining one-third reflects intraspecific and interspecific variation. Animals (Basel). 2021;11(9):2667.

15. doi 10.3390/ani11092667

16. Chadaeva I.V., Filonov S.V., Zolotareva K.A., Khandaev B.M., Ershov N.I., Podkolodnyy N.L., Kozhemyakina R.V., … Stefanova N.A., Kolosova N.G., Markel A.L., Ponomarenko M.P., Oshchepkov D.Y. RatDEGdb: a knowledge base of differentially expressed genes in the rat as a model object in biomedical research. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2023;27(7):794-806. doi 10.18699/VJGB-23-92

17. Che Y., Zhou Z., Shu Y., Zhai C., Zhu Y., Gong S., Cui Y., Wang J.F. Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain. Neurosci Lett. 2015;584:208-213. doi 10.1016/j.neulet.2014.10.031

18. de Nadal E., Ammerer G., Posas F. Controlling gene expression in response to stress. Nat Rev Genet. 2011;12(12):833-845. doi 10.1038/nrg3055

19. Dobin A., Davis C.A., Schlesinger F., Drenkow J., Zaleski C., Jha S., Batut P., Chaisson M., Gingeras T.R. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21. doi 10.1093/bioinformatics/bts635

20. Efron B., Halloran E., Holmes S. Bootstrap confidence levels for phylogenetic trees. Proc Natl Acad Sci USA. 1996;93(23):13429-13434. doi 10.1073/pnas.93.23.13429

21. Evangelista J.E., Xie Z., Marino G.B., Nguyen N., Clarke D.J.B., Ma’ayan A. Enrichr-KG: bridging enrichment analysis across multiple libraries. Nucleic Acids Res. 2023;51(W1):W168-W179. doi 10.1093/nar/gkad393

22. Ferreira N.S., Tostes R.C., Paradis P., Schiffrin E.L. Aldosterone, inflammation, immune system, and hypertension. Am J Hypertens. 2021;34(1):15-27. doi 10.1093/ajh/hpaa137

23. Fontes M.A.P., Marins F.R., Patel T.A., de Paula C.A., Dos Santos Machado L.R., de Sousa Lima E.B., Ventris-Godoy A.C., Viana A.C.R., Linhares I.C.S., Xavier C.H., Filosa J.A., Patel K.P. Neurogenic background for emotional stress-associated hypertension. Curr Hypertens Rep. 2023;25(7):107-116. doi 10.1007/s11906-023-01235-7

24. Fryer C.J., Archer T.K. Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex. Nature. 1998;393(6680):88-91. doi 10.1038/30032

25. Hammer Ø., Harper D.A.T., Ryan P.D. PAST: PAleontological STatistics software package for education and data analysis. Palaeontol Electronica. 2001;4(1):1-9

26. Hering D., Lachowska K., Schlaich M. Role of the sympathetic nervous system in stress-mediated cardiovascular disease. Curr Hypertens Rep. 2015;17(10):80. doi 10.1007/s11906-015-0594-5

27. Hovatta I., Juhila J., Donner J. Oxidative stress in anxiety and comorbid disorders. Neurosci Res. 2010;68(4):261-275. doi 10.1016/j.neures.2010.08.007

28. Jung Y.W., Shim J.I., Shim S.H., Shin Y.J., Shim S.H., Chang S.W., Cha D.H. Global gene expression analysis of cell-free RNA in amniotic fluid from women destined to develop preeclampsia. Medi

29. cine (Baltimore). 2019;98(3):e13971. doi 10.1097/MD.0000000000013971

30. Kinsman B.J., Nation H.N., Stocker S.D. Hypothalamic signaling in body fluid homeostasis and hypertension. Curr Hypertens Rep. 2017;19(6):50. doi 10.1007/s11906-017-0749-7

31. Koper A., Zeef L.A., Joseph L., Kerr K., Gosney J., Lindsay M.A., Booton R. Whole transcriptome analysis of pre-invasive and invasive early squamous lung carcinoma in archival laser microdissected samples. Respir Res. 2017;18(1):12. doi 10.1186/s12931-016-0496-3

32. Lambert A.J., Brand M.D. Reactive oxygen species production by mitochondria. In: Stuart J.A. (Ed.) Mitochondrial DNA. Methods in Molecular Biology™. Vol. 554. Humana Press, 2009;165-181. doi 10.1007/978-1-59745-521-3_11

33. Lambert E.A., Lambert G.W. Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. Curr Hypertens Rep. 2011;13(3):244-248. doi 10.1007/s11906-0110186-y

34. Leek J.T., Johnson W.E., Parker H.S., Jaffe A.E., Storey J.D. The SVA package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28(6):882-883. doi 10.1093/bioinformatics/bts034

35. Leong X.F. Lipid oxidation products on inflammation-mediated hypertension and atherosclerosis: a mini review. Front Nutr. 2021;8:717740. doi 10.3389/fnut.2021.717740

36. Liu H., Zhao Y., Zhao G., Deng Y., Chen Y.E., Zhang J. SWI/SNF complex in vascular smooth muscle cells and its implications in cardiovascular pathologies. Cells. 2024;13(2):168. doi 10.3390/cells13020168

37. Liu M.Y., Li N., Li W.A., Khan H. Association between psychosocial stress and hypertension: a systematic review and meta-analysis. Neurol Res. 2017;39(6):573-580. doi 10.1080/01616412.2017.1317904

38. Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq datawith DESeq2. Genome Biol. 2014;15(12):550. doi 10.1186/s13059-014-0550-8

39. Lu Z. PubMed and beyond: a survey of web tools for searching biomedical literature. Database (Oxford). 2011;baq036. doi 10.1093/database/baq036

40. Ma H., He Y., Bai M., Zhu L., He X., Wang L., Jin T. The genetic polymorphisms of ZC3HC1 and SMARCA4 are associated with hypertension risk. Mol Genet Genomic Med. 2019;7(11):e942. doi 10.1002/mgg3.942

41. Maciejak A., Kiliszek M., Michalak M., Tulacz D., Opolski G., Matlak K., Dobrzycki S., Segiet A., Gora M., Burzynska B. Gene expression profiling reveals potential prognostic biomarkers associated

42. with the progression of heart failure. Genome Med. 2015;7(1):26. doi 10.1186/s13073-015-0149-z

43. Makovka Y.V., Oshchepkov D.Y., Fedoseeva L.A., Markel A.L., Redina O.E. Effect of short-term restraint stress on the expression of genes associated with the response to oxidative stress in the hypothalamus of hypertensive ISIAH and normotensive WAG rats. Antioxidants (Basel). 2024;13(11):1302. doi 10.3390/antiox13111302

44. Maltsev A.V., Evdokimovskii E.V., Kokoz Y.M. α2-Adrenoceptor signaling in cardiomyocytes of spontaneously hypertensive rats starts to impair already at early age. Biochem Biophys Res Commun. 2019;512(4):908-913. doi 10.1016/j.bbrc.2019.03.117

45. Markel A.L. Development of a new strain of rats with inherited stressinduced arterial hypertension. In: Sassard J. (Ed.) Genetic Hypertension. London: John Libbey Eurotext Ltd., 1992;218:405-407

46. Markel A.L., Maslova L.N., Shishkina G.T., Mahanova N.A., Jacobson G.S. Developmental influences on blood pressure regulation in ISIAH rats. In: McCarty R., Blizard D.A., Chevalier R.L. (Eds) Development of the Hypertensive Phenotype: Basic and Clinical Studies. In the series Handbook of Hypertension. Amsterdam: Elsevier, 1999;493-526

47. Markel A.L., Redina O.E., Gilinsky M.A., Dymshits G.M., Kalashnikova E.V., Khvorostova Y.V., Fedoseeva L.A., Jacobson G.S. Neuroendocrine profiling in inherited stress-induced arterial hypertension

48. rat strain with stress-sensitive arterial hypertension. J Endocrinol. 2007;195(3):439-450. doi 10.1677/JOE-07-0254

49. Marques F.Z., Campain A.E., Tomaszewski M., Zukowska-Szczechowska E., Yang Y.H., Charchar F.J., Morris B.J. Gene expression profiling reveals renin mRNA overexpression in human hypertensivekidneys and a role for microRNAs. Hypertension. 2011;58(6): 1093-1098. doi 10.1161/HYPERTENSIONAHA.111.180729

50. Matovic S., Ichiyama A., Igarashi H., Salter E.W., Sunstrum J.K., Wang X.F., Henry M., Kuebler E.S., Vernoux N., Martinez-Trujillo J., Tremblay M.E., Inoue W. Neuronal hypertrophy dampens neuronalintrinsic excitability and stress responsiveness during chronic stress. J Physiol. 2020;598(13):2757-2773. doi 10.1113/JP279666

51. Montezano A.C., Dulak-Lis M., Tsiropoulou S., Harvey A., Briones A.M., Touyz R.M. Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol. 2015;31(5):631-641. doi 10.1016/j.cjca.2015.02.008

52. Mura M., Cecchini M.J., Joseph M., Granton J.T. Osteopontin lung gene expression is a marker of disease severity in pulmonary arterial hypertension. Respirology. 2019;24(11):1104-1110. doi 10.1111/resp.13557

53. Neusser M.A., Lindenmeyer M.T., Moll A.G., Segerer S., Edenhofer I., Sen K., Stiehl D.P., Kretzler M., Grone H.J., Schlondorff D., Cohen C.D. Human nephrosclerosis triggers a hypoxia-related glomerulopathy. Am J Pathol. 2010;176(2):594-607. doi 10.2353/ajpath.2010.090268

54. Orlov S.N. Membrane theory of the pathogenesis of arterial hypertension: what do we know about this, half a century later? Bulletin of Siberian Medicine. 2019;18(2):234-247. doi 10.20538/1682-03632019-2-234-247 (in Russian)

55. Oshchepkov D., Chadaeva I., Kozhemyakina R., Zolotareva K., Khandaev B., Sharypova E., Ponomarenko P., … Kolosova N.G., Nazarenko M., Kolchanov N.A., Markel A., Ponomarenko M. Stress reactivity, susceptibility to hypertension, and differential expression of genes in hypertensive compared to normotensive patients. Int J Mol Sci. 2022;23(5):2835. doi 10.3390/ijms23052835

56. Oshchepkov D.Y., Makovka Y.V., Fedoseeva L.A., Seryapina A.A., Markel A.L., Redina O.E. Effect of short-term restraint stress on the hypothalamic transcriptome profiles of rats with Inherited StressInduced Arterial Hypertension (ISIAH) and normotensive Wistar Albino Glaxo (WAG) rats. Int J Mol Sci. 2024;25(12):6680. doi 10.3390/ijms25126680

57. Patel P.D., Patel G.C., Millar J.C., Feris S., Curry S., Geisert E.E., Clark A.F. Mechanistic insights into glucocorticoid-induced ocular hypertension using differences in mouse strain responsiveness.bioRxiv. 2025. doi 10.1101/2025.07.02.662542

58. Picard M., McEwen B.S. Psychological stress and mitochondria: a systematic review. Psychosom Med. 2018;80(2):141-153. doi 10.1097/PSY.0000000000000545

59. Plaza-Florido A., Altmae S., Esteban F.J., Lof M., Radom-Aizik S., Ortega F.B. Cardiorespiratory fitness in children with overweight/obesity: insights into the molecular mechanisms. Scand J Med Sci Sports. 2021;31(11):2083-2091. doi 10.1111/sms.14028

60. Podkolodnaya O.A., Deryuzhenko M.A., Tverdokhleb N.N., Zolotareva K.A., Makovka Yu.V., Podkolodny N.L., Suslov V.V., … Kondratyuk E.Yu., Redina O.E., Markel A.L., Gruntenko N.E., Ponomarenko M.P. FlyDEGdb knowledge base on differentially expressed genes of Drosophila melanogaster, a model object in biomedicine. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2025;29(7):952-962. doi 10.18699/vjgb-25-101

61. Qiu X., Lin J., Liang B., Chen Y., Liu G., Zheng J. Identification of hub genes and microRNAs associated with idiopathic pulmonary arterial hypertension by integrated bioinformatics analyses. Front Genet. 2021;12:667406. doi 10.3389/fgene.2021.636934

62. Rosenkranz J.A., Venheim E.R., Padival M. Chronic stress causes amygdala hyperexcitability in rodents. Biol Psychiatry. 2010;67(12):1128-1136. doi 10.1016/j.biopsych.2010.02.008

63. Saei H., Govahi A., Abiri A., Eghbali M., Abiri M. Comprehensive transcriptome mining identified the gene expression signature and differentially regulated pathways of the late-onset preeclampsia. Preg nancy Hypertens. 2021;25:91-102. doi 10.1016/j.preghy.2021.05.007

64. Shikhevich S., Chadaeva I., Khandaev B., Kozhemyakina R., Zolotareva K., Kazachek A., Oshchepkov D., … Markel A., Savinkova L., Kolchanov N.A., Kozlov V., Ponomarenko M. Differentially expressed genes and molecular susceptibility to human age-related diseases. Int J Mol Sci. 2023;24(4):3996. doi 10.3390/ijms24043996

65. Spruill T.M. Chronic psychosocial stress and hypertension. Curr Hypertens Rep. 2010;12(1):10-16. doi 10.1007/s11906-009-0084-8

66. Szklarczyk D., Kirsch R., Koutrouli M., Nastou K., Mehryary F., Hachilif R., Gable A.L., Fang T., Doncheva N.T., Pyysalo S., Bork P., Jensen L.J., von Mering C. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638-D646. doi 10.1093/nar/gkac1000

67. Textoris J., Ivorra D., Ben Amara A., Sabatier F., Menard J.P., Heckenroth H., Bretelle F., Mege J.L. Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker. PLoS One. 2013; 8(12):e82638. doi 10.1371/journal.pone.0082638

68. Timmermans S., Souffriau J., Libert C. A general introduction to glucocorticoid biology. Front Immunol. 2019;10:1545. doi 10.3389/fimmu.2019.01545

69. Ulecia-Moron C., Bris A.G., MacDowell K.S., Cervero-Garcia P., Madrigal J.L.M., Garcia-Bueno B., Pereira M.P., Leza J.C., Caso J.R. Chronic mild stress dysregulates autophagy, membrane dynamics, and lysosomal status in frontal cortex and hippocampus of rats. Eur Neuropsychopharmacol. 2025;94:24-35. doi 10.1016/j.euroneuro.2025.02.005

70. Vedi M., Smith J.R., Thomas Hayman G., Tutaj M., Brodie K.C., De Pons J.L., Demos W.M., … Tutaj M.A., Wang S.J., Zacher S., Dwinel M.R., Kwitek A.E. 2022 updates to the Rat Genome Database: a Findable, Accessible, Interoperable, and Reusable (FAIR) resource. Genetics. 2023;224(1):iyad042. doi 10.1093/genetics/iyad042

71. Wallberg A.E., Neely K.E., Hassan A.H., Gustafsson J.A., Workman J.L., Wright A.P. Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor τ1 activation domain. Mol Cell Biol. 2000;20(6):2004-2013. doi 10.1128/MCB.20.6.2004-2013.2000

72. Wu Y.B., Zang W.D., Yao W.Z., Luo Y., Hu B., Wang L., Liang Y.L. Analysis of FOS, BTG2, and NR4A in the function of renal medullary hypertension. Genet Mol Res. 2013;12(3):3735-3741. doi 10.4238/2013.September.19.4

73. Xie Z., Bailey A., Kuleshov M.V., Clarke D.J.B., Evangelista J.E., Jenkins S.L., Lachmann A., Wojciechowicz M.L., Kropiwnicki E., Jagodnik K.M., Jeon M., Ma’ayan A. Gene set knowledge discovery with Enrichr. Curr Protoc. 2021;1(3):e90. doi 10.1002/cpz1.90

74. Yao X., Jing T., Wang T., Gu C., Chen X., Chen F., Feng H., Zhao H., Chen D., Ma W. Molecular characterization and elucidation of pathways to identify novel therapeutic targets in pulmonary arterial hypertension. Front Physiol. 2021;12:694702. doi 10.3389/fphys. 2021.694702

75. Yong H.E., Melton P.E., Johnson M.P., Freed K.A., Kalionis B., Murthi P., Brennecke S.P., Keogh R.J., Moses E.K. Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. PLoS One. 2015;10(5):e0128230. doi 10.1371/journal.pone.0128230

76. Zheng Y., He J.Q. Common differentially expressed genes and pathways correlating both coronary artery disease and atrial fibrillation. EXCLI J. 2021;20:126-141. doi 10.17179/excli2020-3262