Нейрональная NO-синтаза в патогенезе метаболического синдрома

Метаболический синдром (МС), который характеризуется ожирением, гипертонией, дислипидемией, резистентностью к инсулину, приобрел в последние годы характер эпидемии. Вследствие этого изучение молекулярных механизмов, лежащих в основе развития МС и его осложнений, а также поиск новых терапевтических средств для их лечения являются одними из острейших проблем современной эндокринологии. В последние годы получены убедительные свидетельства того, что ключевую роль среди молекулярных причин МС играют функциональные изменения экспрессии, активности и регуляторных свойств нейрональной NO-синтазы (nNOS), катализирующей образование важнейшего вторичного посредника – оксида азота (NO), и зависимых от нее NO/цГМФ-сигнальных путей в мозге, миокарде и скелетных мышцах. В мозге nNOS ассоциирована с NMDA-рецепторами, гиперактивация которых при МС сопровождается избыточной стимуляцией nNOS и гиперпродукцией NO, что приводит к NO-индуцированному повреждению нейронов и нарушению центральной регуляции физиологических процессов и нейродегенерации. В миокарде при МС отмечаются изменения экспрессии и локализации nNOS, а также ее функционального взаимодействия с белками цитоскелета, что ведет к нарушениям сокращения миокарда и гипертрофии. В скелетных мышцах nNOS контролирует их сокращение, окислительный метаболизм, вовлечена в регуляцию расслабления сосудов, а также участвует в регуляции глюкозного транспорта. Снижение экспрессии и активности nNOS, а также дизрегуляция ее активности при МС вызывают нарушения этих процессов, вносят существенный вклад в развитие инсулиновой резистентности и ухудшение глюкозного гомеостаза. Таким образом, nNOS может рассматриваться как важная терапевтическая мишень при лечении МС и других метаболических расстройств, а также для предотвращения их осложнений со стороны нервной и сердечно-сосудистой систем и опорно-двигательного аппарата.

1. Assumpção C.R., Brunini T.M.C., Matsuura C., Resende A.C., Mendes-Ribeiro A.C. Impact of the L-arginine-nitric oxide pathway and oxidative stress on the pathogenesis of the metabolic syndrome. Open Biochem. J. 2008;2:108-115. https://doi.org/10.2174/1874091X00802010108

2. Grundy S.M. Metabolic syndrome: a multiplex cardiovascular risk factor. J. Clin. Endocrinol. Metab. 2007;92:399-404. https://doi.org/10.1210/j.c.2006-0513

3. Mendrick D.L., Diehl A.M., Topor L.S., Dietert R.R., Will Y., La Merrill M.A., Bouret S., Varma V., Hastings K.L., Schug T.T., Hart S.G.E., Burlesson F.G. Metabolic syndrome and associated diseases: from the bench to the clinic. Toxicol. Sci. 2018;162(1):36-42. https://doi.org/10.1093/toxsci/kfx233

4. Кузнецова Л.А. Метаболический синдром: влияние адипокинов на L-аргинин-NO-синтаза-NO сигнальный путь. Acta Biomed. Sci. 2021;6(2):22-40. https://doi.org/10.2941/ABC.2021-.6.2.3

5. Stuehr D.J., Haque M.M. Nitric oxide synthase enzymology in the 20 years after the Nobel Prize. Br. J. Pharmacol. 2019;176(2):177-188. https://doi.org/10.1111/bph.14533

6. Alderton W.K., Cooper C.E., Knowles R.G. Nitric oxide synthases: structure, function and inhibition. Biochem. J. 2001;357:593-615. https://doi.org/10.1042/0264-6021:3570593

7. Carnicer R., Crabtree M.J., Sivakumaran V., Casadei B., Kass D.A. Nitric oxide synthases in heart failure. Antioxid. Redox. Signal. 2013;18(9):1078-1099. https://doi.org/10.1089/ars.2012.4824

8. Zhou L., Zhu D.Y. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide. 2009;20(4):223-230. https://doi.org/10.1016/j.niox.2009.03.001

9. Ahlawat A., Rana A., Goyal N., Sharma S. Potential role of nitric oxide synthase isoforms in pathophysiology of neuropathic pain. Inflammopharmacology. 2014;22(5):269-278. https://doi.org/10.1007/s10787-014-0213-0

10. Suhr F., Gehlert S., Grau M., Bloch W. Skeletal muscle function during exercise-fine-tuning of diverse subsystems by nitric oxide. Int. J. Mol. Sci. 2013;4(4):7109-7139. https://doi.org/10.3390/ijms14047109

11. Maccallini C., Amoroso R. Targeting neuronal nitric oxide synthase as a valuable strategy for the therapy of neurological disorders. Neural. Regen. Res. 2016;11(11):1731-1734. https://doi.org/10.4103/1673-5374.194707

12. Cossenza M., Socodato R., Portugal C.C., Domith I.C.L., Gladulich L.F.H., Encarnacao T.G., Calaza K.C., Mendoca H.R., Campello-Costa P., Paer-de-Carvalho R. Nitric oxide in the nervous system: biochemical, developmental, and neurobiological aspects. Vitam. Horm. 2014;96:79-125. https://doi.org/10.1016/B978-0-12-800254-4.00005-2

13. Jaffrey S.R., Snyder S.H. PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science. 1996;274:774-777. https://doi.org/10.1126/science.274.5288.774

14. Greenwood M.T., Guo Y., Kumar U., Beausejours S., Hussain S.N. Distribution of protein inhibitor of neuronal nitric oxide synthase in rat brain. Biochem. Biophys. Res. Commun. 1997;238(2):617-621. https://doi.org/10.1006/bbrc.1997.7361

15. Ally A., Powell I., Ally M.M., Chaitoff K., Nauli S. Role of neuronal nitric oxide synthase on cardiovascular functions in physiological and pathophysiological states. Nitric Oxide. 2020;102:52-73. https://doi.org/10.1016/j.niox.2020.06.004

16. Wu K.L.H., Chao Y.M., Tsay S.J., Chen C.H., Chan S.H.H., Dovinova I., Chan J.Y. Role of nitric oxide synthase uncoupling at rostral ventrolateral medulla in redox-sensitive hypertension associated with metabolic syndrome. Hypertension. 2014;64:815-824. https://doi.org/10.1161/HYPERTENSIONAHA.114.03777

17. Heinrich T.A., da Silva R.S., Miranda K.M., Switzer C.H., Wink D.A., Fukuto J.M. Biological nitric oxide signalling: chemistry and terminology. Br. J. Pharmacol. 2013;169:1417-1429. https://doi.org/10.1111/bph.12217

18. Cao J., Viholainen J.I., Dart C., Warwick H.K., Leyland M.L., Courtney M.J. The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J. Cell Biol. 2005;168:117-126. https://doi.org/10.1083/jcb.200407024

19. Martínez M.C., Andriantsitohaina R. Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid Redox Signal. 2008;11:669-702. https://doi.org/10.1089/ars.2007.1993

20. Talebi M., İlgün S., Ebrahimi V., Talebi M., Farkhondeh T., Ebrahimi H., Samarghandian S. Zingiber officinale ameliorates Alzheimer’s disease and Cognitive Impairments: Lessons from preclinical studies. Biomed. Pharmacother. 2021;133. https://doi.org/10.1016/j.biopha.2020.111088

21. Collin F. Chemical basis of reactive oxygen species reactivity and involvement in neurodegenerative diseases. Int. J. Mol. Sci. 2019;20:2407. https://doi.org/10.3390/ijms20102407

22. Jung J., Na C., Huh Y. Alterations in nitric oxide synthase in the aged CNS. Oxid. Med. Cell Longev. 2012;2012:718976. https://doi.org/10.1155/2012/718976

23. Colas D., Gharib A., Bezin L., Morales A., Guidon G., Cespuglio R., Sarda N. Regional age-related changes in neuronal nitric oxide synthase (nNOS), messenger RNA levels and activity in SAMP8 brain. BMC Neurosci. 2006;7:81. https://doi.org/10.1186/1471-2202-7-81

24. Zhao D., Watson J.B., Xie C.W. Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J. Neurophysiol. 2004;92:2853-2858. https://doi.org/10.1152/jn.00485.2004

25. Ghosh A., Giese K.P. Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol. Brain. 2015;8:78. https://doi.org/10.1186/s13041-015-0166-2

26. Rameau G.A., Chiu L.Y., Ziff E.B. Bidirectional regulation of neuronal nitric-oxide synthase phosphorylation at serine 847 by the N-methyl-D-aspartate receptor. J. Biol. Chem. 2004;279(14):14307-14314. https://doi.org/10.1074/jbc.M311103200

27. Araki S., Osuka K., Takata T., Tsuchiya T., Watanabe Y. Coordination between calcium/calmodulin-dependent protein kinase ii and neuronal nitric oxide synthase in neurons. Int. J. Mol. Sci. 2020;21(21):7997. https://doi.org/10.3390/ijms21217997

28. Llevenes P., Rodriges-Diez R., Cros-Brunso L., Prieto M.I., Casani L., Balfagon G., Blanco-Rivero J. Beneficial effect of a multistrain synbiotic prodefen plus on the systemic and vascular alterations associated with metabolic syndrome in rats: the role of the neuronal nitric oxide synthase and protein kinase A. Nutrients. 2020;12(1):117. https://doi.org/10.3390/nu12010117

29. Forstermann U., Sessa W.C. Nitric oxide synthases: regulation and function. Eur. Heart J. 2012;33(7):829-837. https://doi.org/10.1093/eurheartj/ehr304

30. Zhang Y.Н., Jang J.H., Wang Y. Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology. J. Physiol. 2014;592(15):3189-3200. https://doi.org/10.1113/jphysiol.2013.270306

31. Tang L., Wang H., Ziolo M.T. Targeting NOS as a therapeutic approach for heart failure. Pharmacol. Ther. 2014; 142(3):306-315. https://doi.org/10.1016/j.pharmthera.2013.12.013

32. Zhang Y.H. Nitric oxide signaling and neuronal nitric oxide synthase in the heart under stress. F1000Res. 2017;6:742. https://doi.org/10.12688/f1000research.10128.1

33. Ashley E.A., Sears C.E., Bryant S.M., Watkins H.C., Casadei B. Cardiac nitric oxide synthase 1 regulates basal and beta-adrenergic contractility in murine ventricular myocytes. Circulation. 2002;105:3011-3016. https://doi.org/10.1161/01.cir.0000019516.31040.2d

34. Dawson D., Lygate C.A., Zhang M.H., Hulber K., Neubauer S., Casadei B. nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation. 2005;112:3729-3737. https://doi.org/10.1161/CIRCULATIONAHA.105.539437

35. Sears C.E., Bryant S.M., Ashley E.A., Lygate C.A., Rakovic S., Wallis H.L., Neubauer S., Terrar D.A., Casadei B. Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. Circ. Res. 2003;92:e52-e59. https://doi.org/10.1161/01.RES.0000064585.95749.6D

36. Barouch L.A., Harrison R.W., Skaf M.W., Rosas G.O., Cappola T.P., Robeissi Z.A., Hobai I.A., Lemmon C.A., Burnett A.L., O`Rourke B., … Hare J.M. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002;416:337-339. https://doi.org/10.1038/416337a

37. Zhang Y.H., Zhang M.H., Sears C.E., Emanuel K., Redwood C., El-Armouche A., KraniasE.G., Casadei B. Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice. Circ. Res. 2008; 102: 242-249. https://doi.org/10.1161/CIRCUESAHA.107.164798

38. Oceandy D., Cartwright E.J., Emerson M., Prehar S., Baudoin F.M., Zi M., Alawi N., Venetucci L., Schuh K., Williams J.C., Armesilla A.L., Neyses L. Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b. Circulation. 2007;115:483-492. https://doi.org/10.1161/CIRCULATIONAHA.106.643791

39. Gonzalez D.R., Beigi F., Treuer A.V., Hare J.M. Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes. Proc. Natl. Acad. Sci. USA. 2007; 104: 20612-20617. https://doi.org/10.1073/pnas.0706796104

40. Khan S.A., Lee K., Minhas K.M., Gonzalez D.R., Raju S.V.Y., Tejani A.D., Li D., Berkowitz D.E., Hare J.M. Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc. Natl. Acad. Sci. USA. 2004;101:15944-15948. https://doi.org/10.1073/pnas.0404136101

41. Lee Y., Chakraborty S., Muthuchamy M. Roles of sarcoplasmic reticulum Ca 2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model. Sci. Rep. 2020;10:12320. https://doi.org/10.1038/s41598-020-69196-4

42. Dineen S.L., McKenney M.L., Bell L.N., Fullenkamp A.M., Schultz K.A., Allosh M., Chalasani N., Sturek M. Metabolic syndrome abolishes glucagonlike peptide 1 receptor agonist stimulation of SERCA in coronary smooth muscle. Diabetes. 2015;64:3321-3327. https://doi.org/10.2337/db14-1790

43. Herring N., Paterson D.J. Neuromodulators of peripheral cardiac sympatho-vagal balance. Exp. Physiol. 2009;94:46-53. https://doi.org/10.1113/expphysiol.2008.044776

44. Johnson E.K., Zhang L., Adams M.E., Phillips A., Freitas M.A., Froehner S.C., Green-Church K.B., Montanazo F. Proteomic analysis reveals new cardiacspecific dystrophin-associated proteins. PLoS One. 2012;7(8): e43515. https://doi.org/10.1371/journal.pone.0043515

45. Melikian N., Seddon M.D., Casadei B., Chowienczyk P.J., Shah A.M. Neuronal nitric oxide synthase and human vascular regulation. Trends Cardiovasc. Med. 2009;19:256-262. https://doi.org/10.1016/j.tcm.2010.02.007

46. Li F.C., Chan J.Y., Chan S.H., Chang A.Y. In the rostral ventrolateral medulla, the 70-kDa heat shock protein (HSP70), but not HSP90, confers neuroprotection against fatal endotoxemia via augmentation of nitric-oxide synthase I (NOS I)/protein kinase G signaling pathway and inhibition of NOS II/peroxynitrite cascade. Mol. Pharmacol. 2005;68:179-192. https://doi.org/10.1124/mol.105.011684

47. Piech A., Dessy C., Havaux X., Feron O., Balligand J.L. Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats. Cardiovasc. Res. 2003;57:456-467. https://doi.org/10.1016/s0008-6363(02)00676-4

48. Fridolfsson H.N., Patel H.H. Caveolin and caveolae in age associated cardiovascular disease. J. Geriatr. Cardiol. 2013;10:66-74. https://doi.org/10.3969/j.issn.1671-5411.2013.01.011

49. Forstermann U., Xia N., Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res. 2017; 120: 713-735. https://doi.org/10.1161/CIRCRESAHA.116.309326

50. Jian Z., Han H., Zhang T., Puglisi J., Izu L.T., Onafiok E., Erickson J.R., ChenY.-J., Horvath B., Shimkunas R., … Chen-Izu Y. Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling. Sci. Signal. 2014;7:27. https://doi.org/10.1126/scisignal.2005046

51. Pourbagher-Shahri A.M., Farkhondeh T., Talebi M., Kopustinskiene D.M., Samarghandian S., Bernatoniene J. An overview of NO signaling pathways in aging. Molecules. 2021;26(15):4533. https://doi.org/10.3390/molecules26154533

52. Yu Q., Gao F., Ma X.L. Insulin says NO to cardiovascular disease. Cardiovasc. Res. 2011;89:516-524. https://doi.org/10.1093/cvr/cvq349

53. Shabeeh H., Khan S., Jiang B., Brett S., Melikian N., Casadei B., Chowienczyk P.J., Shan A.M. Blood pressure in healthy humans is regulated by neuronal NO synthase. Hypertension. 2017;69:970-976. https://doi.org/10.1161/HYPERTENSIONAHA.116.08792

54. Fadel P.J. Nitric oxide and cardiovascular regulation: beyond the endothelium. Hypertension. 2017;69:778-779. https://doi.org/10.1161/HYPERTENSIONAHA.117.08999

55. Zhang Y.H. Neuronal nitric oxide synthase in hypertension - an update. Clin. Hypertens. 2016;22:20. https://doi.org/10.1186/S40885-016-0055-8

56. Costa E.D., Rezende B.A., Cortes S.F., Lemos V.S. Neuronal nitric oxide synthase in vascular physiology and diseases. Front. Physiol. 2016;7:206. https://doi.org/10.3389/FPHYS.2016.00206

57. Niu X., Watts V.L., Cingolani O.H., Sivakumaran V., Leyton-Mange J.S., Ellis C.L., Miller K.L., Vandegaer K., Bedja D., Gabrielson K.I., … Barouch L.A. Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase. J. Am. Coll. Cardiol. 2012;59(22):1979-1987. https://doi.org/10.1016/j.jacc.2011.12.046

58. Gantner B.N., LaFond K.M., Bonini M.G. Nitric oxide in cellular adaptation and disease. Redox Biol. 2020;34:101550. https://doi.org/10.1016/j.redox.2020.101550

59. Watts V.L., Sepulveda F.M., Cingolani O.H., Ho A.S., Niu X., Kim R., Miller K.L., Vandegaer K., Bedja D., Gabrielson K.I., … Barouch L.A. Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation. J. Mol. Cell Cardiol. 2013;62:8-17. https://doi.org/10.1016/j.yjmcc.2013.04.025

60. Lane P., Gross S.S. The autoinhibitory control element and calmodulin conspire to provide physiological modulation of endothelial and neuronal nitric oxide synthase activity. Acta Physiol. Scand. 2000;168:53-63. https://doi.org/10.1046/j.1365-201x.2000.00654.x

61. Napp A., Brixius K.., Pott C., Ziskoven C., Boelck B., Mehlhorn U., Schwinger R.H.G., Bloch W. Effects of the beta3-adrenergic agonist BRL 37344 on endothelial nitric oxide synthase phosphorylation and force of contraction in human failing myocardium. J. Card. Fail. 2009;15:57-67. https://doi.org/10.1016/j.cardfail.2008.08.006

62. Niu X., Zhao L., Li X., Xue Y., Wang B., Lv Z., Chen J., Sun D., Zheng Q. β3-Adrenoreceptor stimulation protects against myocardial infarction injury via eNOS and nNOS activation. PLoS One. 2014;9(6):e98713. https://doi.org/10.1371/journal.Pone.0098713

63. Hirai D.M., Copp S.W., Ferguson S.K., Holdsworth C.T., Hageman K.S., Poole D.C., Musch T.I. Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia: exercise training and moderate compensated heart failure. Nitric. Oxide. 2013;74:1-9. https://doi.org/10.1016/j.niox.2017.12.008

64. Hinchee-Rodriguez K., Garg N., Venkatakrishnan P., Roman M.G., Adamo M.L., Masters B.S., Romam L.J. Neuronal nitric oxide synthase is phosphorylated in response to insulin stimulation in skeletal muscle. Biochem. Biophys. Res. Commun. 2013;435(3):501-505. https://doi.org/10.1016/j.bbrc.2013.05.020

65. Eghbalzadeh K., Brixius K., Bloch W., Brinkmann C. Skeletal muscle nitric oxide (NO) synthases and NO-signaling in “diabesity”-hat about the relevance of exercise training interventions? Nitric Oxide. 2014;37 :28-40. 10.1016/j.niox.2013.12.009

66. Balke J.E., Zhang L., Percival J.M. Neuronal nitric oxide synthase (nNOS) splice variant function: Insights into nitric oxide signaling from skeletal muscle. Nitric Oxide. 2019;82:35-47. https://doi.org/10.1016/j.niox.2018.11.004

67. Lai Y., Zhao J., Yue Y., Duan D. α2 and α3 helices of dystrophin R16 and R17 frame a microdomain in the α1 helix of dystrophin R17 for neuronal NOS binding. Proc. Natl. Acad. Sci. 2013;110:525-530. https://doi.org/10.1016/pnas.1211431109

68. Wehling-Henricks M., Tidball J.G. Neuronal nitric oxide synthase-rescue of dystrophin/utrophin double knockout mice does not require nNOS localization to the cell membrane. PLoS One. 2011;6:e25071. https://doi.org/10.1371/journal.pone.0025071

69. Terradas A.L., Vitadello M., Traini L., Namuduri A.V., Gastaldello S., Gorza L. Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress-dependent, early event driving disuse atrophy. J. Pathol. 2018;246(4):433-446. https://doi.org/10.1002/path.5149

70. Meinen S., Lin S., Ruegg M.A., Punda A.R. Fatigue and muscle atrophy in a mouse model of myasthenia gravis is paralleled by loss of sarcolemmal nNOS. PLoS One. 2012;7:e44148. https://doi.org/10.1371/journal.pone.0044148

71. Baldelli S., Barbato L.D., Tatulli G., Aquilano K., Ciriolo M.R. The role of nNOS and PGC-1α in skeletal muscle cells. J. Cell Sci. 2014;127(Pt 22):4813-4820. https://doi.org/10.1242/jcs.154229

72. Stephens T.J., Canny B.J., Snow R.J., McConell G.K. 5′-Aminoimidazole-4-carboxyamide-ribonucleoside-activated glucose transport is not prevented by nitric oxide synthase in rat isolated skeletal muscle. Clin. Exp. Pharmacol. Physiol. 2004;31(7):419-423. https://doi.org/10.1111/j.1440-1681.2004.04014.x

73. Samengo G., Avik A., Fedor B., Whittaker D., Myung K.H., Wehling-Henricks M., Tidball J.G. Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia. Aging. Cell. 2012;11:1036-1045. https://doi.org/10.1111/acel.12003

74. Kellogg D.L., McCammon K.M., Hinchee-Rodriguez K.S., Adamo M.L., Roman L.J. Neuronal nitric oxide synthase mediates insulin- and oxidative stress-induced glucose uptake in skeletal muscle myotubes. Free Radic. Biol. Med. 2017;110:261-269. https://doi.org/10.1016/j.freeradbiomed.2017.06.018

75. Matheny R.W., Adamo M.L. Current perspectives on Akt Akt-ivation and Akt-ions. Exp. Biol. Med. (Maywood). 2009;234(11):1264-1270. https://doi.org/10.3181/0904-MR-138

76. Kaur J. A comprehensive review on metabolic syndrome. Cardiol. Res. Pract. 2014; 2014: 943162. https://doi.org/10.1155/2014/943162

77. Hashim K.N., Chin K.Y., Ahmad F. The mechanism of honey in reversing metabolic syndrome. Molecules. 2021;26(4):808. https://doi.org/10.3390/molecules26040808

78. Lemieux I., Despres J.P. Metabolic syndrome: past, present and future. Nutrients. 2020;12(11):3501. https://doi.org/10.3390/nu12113501

79. Saklayen M.G. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 2018;20:12. https://doi.org/10.1007/s11906-018-0812-z

80. Rochlani Y., Pothineni N.V., Kovelamudi S., Mehta J.L. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther. Adv. Cardiovasc. 2017;11(8):215-225. https://doi.org/10.1177/1753944717711379

81. Soodaeva S., Klimakov I., Kubysheva N., Popova N., Batyrshin I. The state of the nitric oxide cycle in respiratory tract diseases. Oxid. Med. Cell. Longev. 2020;2020:4859260. https://doi.org/10.1155/2020/4859260

82. Меньщикова Е.Б., Зенков Н.К., Реутов В.П. Оксид азота и NO-синтазы в организме млекопитающих при различных функциональных состояниях. Биохимия. 2000;65(4):485-503.

83. Lundberg J.O., Gladwin M.T., Shiva S., Ahluwalia A., Webb A.J., Benjamin N., Bryan N.S., Butler A., Cabrales P., Fago A., … Weitzberg E. Nitrate and nitrite in biology, nutrition and therapeutics. Nature Chemical Biology. 2009;5(12):865-869. https://doi.org/10.1038/nchembio.260

84. Peутов В.П., Самосудова Н.В., Сорокина Е.Г. Модель глутаматной нейротоксичности и механизмы развития типового патологического процесса. Биофизика. 2019;64(2):316-336. https://doi.org/10.1134/S000630291902011X

85. Kapil V., Khambata R.S., Jones D.A., Rathod K., Primus C., Massimo G., Fukuto J.M., Ahluwalia A. The noncanonical pathway for in vivo nitric oxide generation: the nitrate-nitrite-nitric oxide pathway. Pharmacol. Rev. 2020;72(3):692-766. https://doi.org/10.1124/pr.120.019240

86. Stefano G.B., Kream R.M. Alkaloids, nitric oxide, and nitrite reductases: evolutionary coupling as regulators of cellular bioenergetics with special relevance to the human microbiome. Med. Sci. Monit. 2018;24:3153-3158. https://doi.org/10.12659/MSM.909409

87. Kayki-Mutlu G., Koch W.J. Nitric oxide and S-nitrosylation in cardiac regulation: G protein-coupled receptor kinase-2 and β-arrestins as targets. Int. J. Mol. Sci. 2021;22(2):521. https://doi.org/10.3390/ijms22020521