Возможные генетически детерминированные механизмы развития артериальной гипертонии при табакокурении

Рост распространенности артериальной гипертонии/гипертензии (АГ) в популяциях, недостаточная эффективность лечения, необходимость стратификации рисков, профилактики, ранней диагностики и эффективного лечения актуализируют геномные исследования для разработки персонализированного терапевтического подхода к АГ. В обзоре исследуются возможные генетически детерминированные механизмы развития АГ и эндотелиальной дисфункции, обусловленные полиморфизмом генов эндотелиальной синтазы окиси азота (еNOS) и ферментов фаз I и II системы детоксикации ксенобиотиков. Обсуждается вероятное взаимодействие обеих систем при воздействии вредных экологических факторов, в том числе табакокурения, и в гестационном периоде. Предлагается изучать гены-кандидаты АГ в системе детоксикации ксенобиотиков, носительство различных вариантов которых может определять чувствительность либо резистентность к антигипертензивной фармакотерапии, что может быть полезно для разработки персонализированной тактики ведения больных АГ.

1. Чазова И. Е., Жернакова Ю. В., Ощепкова Е. В., Шальнова С. А., Яровая Е. Б., Конради А. О. и др. Распространенность факторов риска сердечнососудистых заболеваний в российской популяции больных артериальной гипертонией. Кардиология. 2014;54(10):4–12.

2. Бокарев И. Н., Дулин П. А., Овчинников Ю. В., Симоненко В. Б. Артериальная гипертония: современное состояние проблемы. Клиническая медицина. 2017;95(7):581–5. DOI: 10.18821/00232149-2017-95-7-581-585

3. Howard G. Cigarette Smoking and Progression of Atherosclerosis: Te Atherosclerosis Risk in Communities (ARIC) Study. JAMA. 1998;279(2):119. DOI: 10.1001/jama.279.2.119

4. Barnoya J, Glantz SA. Cardiovascular Effects of Secondhand Smoke: Nearly as Large as Smoking. Circulation. 2005;111(20):2684–98. DOI: 10.1161/CIRCULATIONAHA.104.492215

5. Smith C. Particulate and vapor phase constituents of cigarete mainstream smoke and risk of myocardial infarction. Atherosclerosis. 2001;158(2):257–67. DOI: 10.1016/S0021-9150(01)00570-6

6. Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, Shackelford K, Steiner C, Heuton KR et al. Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Te Lancet. 2014;384(9947):980–1004. DOI: 10.1016/S0140-6736(14)60696-6

7. Banderali G, Martelli A, Landi M, Moreti F, Beti F, Radaelli G et al. Short and long term health effects of parental tobacco smoking during pregnancy and lactation: a descriptive review. Journal of Translational Medicine. 2015;13(1). DOI: 10.1186/s12967-015-0690-y

8. Furchgot RF, Zawadzki JV. Te obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6. DOI: 10.1038/288373a0

9. Cherry PD, Furchgot RF, Zawadzki JV, Jothianandan D. Role of endothelial cells in relaxation of isolated arteries by bradykinin. Proceedings of the National Academy of Sciences. 1982;79(6):2106–10. DOI: 10.1073/pnas.79.6.2106

10. Kang K-T. Endothelium-derived Relaxing Factors of Small Resistance Arteries in Hypertension. Toxicological Research. 2014;30(3):141–8. DOI: 10.5487/TR.2014.30.3.141

11. Cooke, MD JP, Dzau, MD VJ. Nitric oxide synthase: Role in the Genesis of Vascular Disease. Annual Review of Medicine. 1997;48(1):489–509. DOI: 10.1146/annurev.med.48.1.489

12. Yallampalli C, Garfeld RE. Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. American Journal of Obstetrics and Gynecology. 1993;169(5):1316–20. DOI: 10.1016/0002-9378(93)90299-X

13. Robinson LJ, Weremowicz S, Morton CC, Michel T. Isolation and Chromosomal Localization of the Human Endothelial Nitric Oxide Synthase (NOS3) Gene. Genomics. 1994;19(2):350–7. DOI: 10.1006/geno.1994.1068

14. Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. Te Journal of Biological Chemistry. 1993;268(23):17478–88. PMID: 7688726

15. Tesauro M, Tompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: Cleavage of proteins with aspartate vs. glutamate at position 298. Proceedings of the National Academy of Sciences. 2000;97(6):2832–5. DOI: 10.1073/pnas.97.6.2832

16. Ahsan A, Norboo T, Baig MA, Qadar Pasha MA. Simultaneous Selection of the Wild-type Genotypes of the G894T and 4B/4A Polymorphisms of NOS3 Associate with High-altitude Adaptation. Annals of Human Genetics. 2005;69(3):260–7. DOI: 10.1046/j.1529-8817.2005.00158.x

17. Cai H, Wilcken DEL, Wang XL. Te Glu-298→Asp (894G→T) mutation at exon 7 of the endothelial nitric oxide synthase gene and coronary artery disease. Journal of Molecular Medicine. 1999;77(6):511–4. DOI: 10.1007/s001099900020

18. Akomolafe A, Luneta K, Erlich P, Cupples L, Baldwin C, Huyck M et al. Genetic association between endothelial nitric oxide synthase and Alzheimer disease. Clinical Genetics. 2006;70(1):49–56. DOI: 10.1111/j.1399-0004.2006.00638.x

19. Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A et al. A Common Variant of the Endothelial Nitric Oxide Synthase (Glu298→Asp) Is a Major Risk Factor for Coronary Artery Disease in the UK. Circulation. 1999;100(14):1515–20. DOI: 10.1161/01.CIR.100.14.1515

20. Berger K, Stögbauer F, Stoll M, Wellmann J, Huge A, Cheng S et al. Te glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case–control studies. Human Genetics. 2007;121(2):169–78. DOI: 10.1007/s00439006-0302-2

21. Kobashi G, Yamada H, Ohta K, Kato E-H, Ebina Y, Fujimoto S. Endothelial nitric oxide synthase gene (NOS3) variant and hypertension in pregnancy. American Journal of Medical Genetics. 2001;103(3):241–4. DOI: 10.1002/ajmg.1535

22. Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H et al. T-786→C Mutation in the 5′-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated with Coronary Spasm. Circulation. 1999;99(22):2864–70. DOI: 10.1161/01.CIR.99.22.2864

23. Gamil S, Erdmann J, Abdalrahman IB, Mohamed AO. Association of NOS3 gene polymorphisms with essential hypertension in Sudanese patients: a case control study. BMC Medical Genetics. 2017;18(1). DOI: 10.1186/s12881-017-0491-7

24. Muniz L, Luizon MR, Palei ACT, Lacchini R, Duarte G, Cavalli RC et al. eNOS Tag SNP Haplotypes in Hypertensive Disorders of Pregnancy. DNA and Cell Biology. 2012;31(12):1665–70. DOI: 10.1089/dna.2012.1768

25. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995;377(6546):239–42. DOI: 10.1038/377239a0

26. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. Journal of Clinical Investigation. 1998;101(4):731–6. DOI: 10.1172/JCI1699

27. Channon KM, Qian H, George SE. Nitric Oxide Synthase in Atherosclerosis and Vascular Injury: Insights from Experimental Gene Terapy. Arteriosclerosis, Trombosis, and Vascular Biology. 2000;20(8):1873–81. DOI: 10.1161/01.ATV.20.8.1873

28. Shesely EG, Gilbert C, Granderson G, Carretero CD, Carretero OA, Beierwaltes WH. Nitric oxide synthase gene knockout mice do not become hypertensive during pregnancy. American Journal of Obstetrics and Gynecology. 2001;185(5):1198–203. DOI: 10.1067/mob.2001.118142

29. Touyz RM. Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension: What Is the Clinical Signifcance? Hypertension. 2004;44(3):248–52. DOI: 10.1161/01.HYP.0000138070.47616.9d

30. Wilcox CS, Pearlman A. Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides. Pharmacological Reviews. 2008;60(4):418– 69. DOI: 10.1124/pr.108.000240

31. Sanchez-Aranguren LC, Prada CE, Riano-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia: role of oxidative stress. Frontiers in Physiology. 2014;5. DOI: 10.3389/fphys.2014.00372

32. Fleming I, Michaelis UR, Bredenköter D, Fisslthaler B, Dehghani F, Brandes RP et al. Endothelium-Derived Hyperpolarizing Factor Synthase (Cytochrome P450 2C9) Is a Functionally Signifcant Source of Reactive Oxygen Species in Coronary Arteries. Circulation Research. 2001;88(1):44–51. DOI: 10.1161/01.RES.88.1.44

33. Büssemaker E, Popp R, Fisslthaler B, Larson CM, Fleming I, Busse R et al. Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery. Hypertension. 2003;42(4):562–8. DOI: 10.1161/01.HYP.0000088852.28814.E2

34. Vasudevan H, Yuen VG, McNeill JH. Testosterone-dependent increase in blood pressure is mediated by elevated Cyp4A expression in fructosefed rats. Molecular and Cellular Biochemistry. 2012;359(1–2):409–18. DOI: 10.1007/s11010-011-1035-7

35. Chen P, Guo M, Wygle D, Edwards PA, Falck JR, Roman RJ et al. Inhibitors of Cytochrome P450 4A Suppress Angiogenic Responses. Te American Journal of Pathology. 2005;166(2):615–24. DOI: 10.1016/S00029440(10)62282-1

36. Webler AC, Popp R, Korff T, Michaelis UR, Urbich C, Busse R et al. Cytochrome P450 2C9-Induced Angiogenesis Is Dependent on EphB4. Arteriosclerosis, Trombosis, and Vascular Biology. 2008;28(6):1123–9. DOI: 10.1161/ATVBAHA.107.161190

37. Jennings BL, George LW, Pingili AK, Khan NS, Estes AM, Fang XR et al. Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice. Hypertension. 2014;64(1):134–40. DOI: 10.1161/HYPERTENSIONAHA.114.03275

38. Ma Y, Ni W, Zhu W, Xiong Y, Deng X. Association of genetic polymorphisms of CYP 2C19 with hypertension in a Chinese Han population. Blood Pressure. 2011;20(3):166–70. DOI: 10.3109/08037051.2010.542640

39. Schäfer A, Galuppo P, Fraccarollo D, Vogt C, Widder JD, Pfrang J et al. Increased Cytochrome P4502E1 Expression and Altered Hydroxyeicosatetraenoic Acid Formation Mediate Diabetic Vascular Dysfunction: Rescue by Guanylyl-Cyclase Activation. Diabetes. 2010;59(8):2001–9. DOI: 10.2337/db09-1668

40. Gergel’ D, Mišık V, Riesz P, Cederbaum AI. Inhibition of Rat and Human Cytochrome P4502E1 Catalytic Activity and Reactive Oxygen Radical Formation by Nitric Oxide. Archives of Biochemistry and Biophysics. 1997;337(2):239–50. DOI: 10.1006/abbi.1996.9765

41. Hillig T, Krustrup P, Fleming I, Osada T, Saltin B, Hellsten Y. Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans. Te Journal of Physiology. 2003;546(1):307–14. DOI: 10.1113/jphysiol.2002.030833

42. Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I. Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease. Circulation. 2004;109(2):178–83. DOI: 10.1161/01.CIR.0000105763.51286.7F

43. Garrick R, Woodin BR, Stegeman JJ. Cytochrome p4501a induced differentially in endothelial cells cultured from different organs of Anguilla rostrata. In Vitro Cellular & Developmental Biology Animal. 2005;41(1):57. DOI: 10.1290/0409063.1

44. Guiney PD, Smolowitz RM, Peterson RE, Stegeman JJ. Correlation of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induction of Cytochrome P4501A in Vascular Endothelium with Toxicity in Early Life Stages of Lake Trout. Toxicology and Applied Pharmacology. 1997;143(2):256–73. DOI: 10.1006/taap.1996.8051

45. Schlezinger JJ, Stegeman JJ. Dose and inducer-dependent induction of cytochrome P450 1A in endothelia of the eel, including in the swimbladder rete mirabile, a model microvascular structure. Drug Metabolism and Disposition: Te Biological Fate of Chemicals. 2000;28(6):701–8. PMID: 10820144

46. Kopf PG, Walker MK. 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1. Toxicology and Applied Pharmacology. 2010;245(1):91–9. DOI: 10.1016/j.taap.2010.02.007

47. Zangar R. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicology and Applied Pharmacology. 2004;199(3):316–31. DOI: 10.1016/j.taap.2004.01.018

48. Fleming I, Bauersachs J, Schafer A, Scholz D, Aldershvile J, Busse R. Isometric contraction induces the Ca2+-independent activation of the endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences. 1999;96(3):1123–8. DOI: 10.1073/pnas.96.3.1123

49. Kopf PG, Scot JA, Agbor LN, Boberg JR, Elased KM, Huwe JK et al. Cytochrome P4501A1 Is Required for Vascular Dysfunction and Hypertension Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Toxicological Sciences. 2010;117(2):537–46. DOI: 10.1093/toxsci/kfq218

50. Stoll M. New Target Regions for Human Hypertension via Comparative Genomics. Genome Research. 2000;10(4):473–82. DOI: 10.1101/gr.10.4.473

51. Gambier N, Marteau J-B, Bat A-M, Marie B, Tompson A, Siest G et al. Interaction between CYP1A1 T3801C and AHR G1661A polymorphisms according to smoking status on blood pressure in the Stanislas cohort: Journal of Hypertension. 2006;24(11):2199–205. DOI: 10.1097/01.hjh.0000249697.26983.aa

52. O’Toole TE, Conklin DJ, Bhatnagar A. Environmental Risk Factors for Heart Disease. Reviews on Environmental Health. 2008;23(3):167–202. DOI: 10.1515/REVEH.2008.23.3.167

53. Kang HK, Dalager NA, Needham LL, Paterson DG, Lees PSJ, Yates K et al. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American Journal of Industrial Medicine. 2006;49(11):875–84. DOI: 10.1002/ajim.20385

54. Dalton TP, Kerzee JK, Wang B, Miller M, Dieter MZ, Lorenz JN et al. Dioxin exposure is an environmental risk factor for ischemic heart disease. Cardiovascular Toxicology. 2001;1(4):285–98. PMID: 12213967

55. Kopf PG, Huwe JK, Walker MK. Hypertension, Cardiac Hypertrophy, and Impaired Vascular Relaxation Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin are Associated with Increased Superoxide. Cardiovascular Toxicology. 2008;8(4):181–93. DOI: 10.1007/s12012-008-9027-x

56. Eckers A, Haendeler J. Endothelial Cells in Health and Disease. Antioxidants & Redox Signaling. 2015;22(14):1209–11. DOI: 10.1089/ars.2015.6323

57. Reszka E, Wasowicz W. Signifcance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk. International Journal of Occupational Medicine and Environmental Health. 2001;14(2):99–113. PMID: 11548073

58. Engel LS. Pooled Analysis and Meta-analysis of Glutathione S-Transferase M1 and Bladder Cancer: A HuGE Review. American Journal of Epidemiology. 2002;156(2):95–109. DOI: 10.1093/aje/kwf018

59. Cao W, Cai L, Rao J-Y, Pantuck A, Lu M-L, Dalbagni G et al. Tobacco smoking,GSTP1 polymorphism, and bladder carcinoma. Cancer. 2005;104(11):2400–8. DOI: 10.1002/cncr.21446

60. Maseti S, Boto N, Manfredi S, Colombo MG, Rizza A, Vassalle C et al. Interactive effect of the glutathione S-transferase genes and cigarete smoking on occurrence and severity of coronary artery risk. Journal of Molecular Medicine. 2003;81(8):488–94. DOI: 10.1007/s00109-0030448-5

61. Wilson MH, Grant PJ, Hardie LJ, Wild CP. Glutathione S-transferase M1 null genotype is associated with a decreased risk of myocardial infarction. Te FASEB Journal. 2000;14(5):791–6. DOI: 10.1096/fasebj.14.5.791

62. Berhane K, Widersten M, Engstrom A, Kozarich JW, Mannervik B. Detoxication of base propenals and other alpha, beta-unsaturated aldehyde products of radical reactions and lipid peroxidation by human glutathione transferases. Proceedings of the National Academy of Sciences. 1994;91(4):1480–4. DOI: 10.1073/pnas.91.4.1480

63. Conklin DJ, Haberzetl P, Prough R, Bhatnagar A. Glutathione-Stransferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. American Journal of Physiology-Heart and Circulatory Physiology. 2009;296(5):H1586–97. DOI: 10.1152/ajpheart.00867.2008

64. Frohlich ED, Dustan HP, Bumpus FM. Te celebration of a leader. Hypertension. 1991;18(4):443–5. DOI: 10.1161/01.HYP.18.4.443

65. Padmanabhan S, Caulfeld M, Dominiczak AF. Genetic and Molecular Aspects of Hypertension. Circulation Research. 2015;116(6):937–59. DOI: 10.1161/CIRCRESAHA.116.303647

66. Savoia C, Volpe M, Grassi G, Borghi C, Agabiti Rosei E, Touyz RM. Personalized medicine—a modern approach for the diagnosis and management of hypertension. Clinical Science. 2017;131(22):2671–85. DOI: 10.1042/CS20160407