Патофизиологическая и клиническая значимость нарушений минерального гомеостаза в контексте развития сердечно-сосудистых заболеваний

Негативные тенденции заболеваемости и смертности от сердечно-сосудистых заболеваний определяют актуальность поиска патогенетических механизмов, воздействие на которые могло бы повысить эффективность профилактических мероприятий. Рост смертности от болезней системы кровообращения в значительной степени обусловлен увеличением доли пациентов с коморбидными патологиями, среди которых высокой распространенностью характеризуются нарушения минерального гомеостаза. Одним из центральных механизмов поддержания минерального гомеостаза крови являются кальций-фосфатные бионы (кальципротеиновые частицы, КФБ) – минерало-органические частицы, формирующиеся в крови при связывании минерального шаперона фетуина-А с зарождающимися кристаллами фосфата кальция. Физиологический смысл формирования КФБ заключается в агрегации избыточных ионов кальция и фосфора, их своевременном выведении и защите организма от внескелетной кальцификации. В то же время в процессе своей циркуляции в кровотоке КФБ интернализуются артериальными эндотелиальными клетками и вызывают дисфункцию эндотелия вследствие его провоспалительной активации, эндотелиально-мезенхимального перехода и нарушения эндотелиальной механотрансдукции. Исследования на лабораторных животных показали, что регулярное внутривенное введение КФБ приводит к формированию неоинтимы в отсутствие иных факторов сердечно-сосудистого риска, подтверждая патофизиологическую значимость вызываемой КФБ дисфункции эндотелия. Помимо формирования неоинтимы, регулярное внутривенное введение КФБ также провоцирует развитие адвентициального и околососудистого воспаления. Таким образом, при циркуляции в крови КФБ оказывают выраженное патогенное действие как на артериальный эндотелий, так и на артерии в целом. Проведенные в последние годы исследования свидетельствуют в пользу клинической значимости избыточного формирования КФБ в крови, поскольку оно ассоциировано с развитием артериальной гипертензии, инфаркта миокарда, хронической ишемии головного мозга, ишемического инсульта и с сердечно-сосудистой смертью у субъектов с нормальной функцией почек, а также с развитием заболеваний периферических артерий, инфаркта миокарда и сердечно-сосудистой смертью у пациентов с терминальной хронической почечной недостаточностью, в том числе после трансплантации почки. Кроме того, ускоренное формирование КФБ в крови коррелирует с развитием острых сердечно-сосудистых событий и у пациентов с более ранними стадиями хронической болезни почек. В обзоре всестороннее обсуждаются как результаты изучения патологических послед ствий формирования КФБ в крови и исследования молекулярных механизмов их патогенного действия, так и потенциальные возможности влиять на эти процессы при помощи активно разрабатываемых в настоящее время терапевтических вмешательств. 

1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, Bonny A, Brauer M, Brodmann M, Cahill TJ, Carapetis J, Catapano AL, Chugh SS, Cooper LT, Coresh J, Criqui M, DeCleene N, Eagle KA, Emmons-Bell S, Feigin VL, Fernández-Solà J, Fowkes G, Gakidou E, Grundy SM, He FJ, Howard G, Hu F, Inker L, Karthikeyan G, Kassebaum N, Koroshetz W, Lavie C, Lloyd-Jones D, Lu HS, Mirijello A, Temesgen AM, Mokdad A, Moran AE, Muntner P, Narula J, Neal B, Ntsekhe M, Moraes de Oliveira G, Otto C, Owolabi M, Pratt M, Rajagopalan S, Reitsma M, Ribeiro ALP, Rigotti N, Rodgers A, Sable C, Shakil S, Sliwa-Hahnle K, Stark B, Sundström J, Timpel P, Tleyjeh IM, Valgimigli M, Vos T, Whelton PK, Yacoub M, Zuhlke L, Murray C, Fuster V; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global Burden of Cardiovas cular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982-3021. https://doi.org/10.1016/j.jacc.2020.11.010

2. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736-1788. https://doi.org/10.1016/S0140-6736(18)32203-7

3. Buddeke J, Bots ML, van Dis I, Liem A, Visseren FLJ, Vaartjes I. Trends in comorbidity in patients hospitalised for cardiovascular disease. Int J Cardiol. 2017;248:382-388. https://doi.org/10.1016/j.ijcard.2017.06.106

4. Rahimi K, Lam CSP, Steinhubl S. Cardiovascular disease and multimorbidity: A call for interdisciplinary research and personalized cardiovascular care. PLoS Med. 2018;15(3):e1002545. https://doi.org/10.1371/journal.pmed.1002545

5. Crowe F, Zemedikun DT, Okoth K, Adderley NJ, Rudge G, Sheldon M, Nirantharakumar K, Marshall T. Comorbidity phenotypes and risk of mortality in patients with ischaemic heart disease in the UK. Heart. 2020;106(11):810-816. https://doi.org/10.1136/heartjnl-2019-316091

6. Cruz-Ávila HA, Vallejo M, Martínez-García M, Hernández-Lemus E. Comorbidity Networks in Cardiovascular Diseases. Front Physiol. 2020;11:1009. https://doi.org/10.3389/fphys.2020.01009

7. Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol. 1997;50(8):967-73. https://doi.org/10.1016/s0895-4356(97)00104-2

8. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And Recurrent Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112(17):2627-33. https://doi.org/10.1161/CIRCULATIONAHA.105.553198

9. Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2008;156(3):556-63. https://doi.org/10.1016/j.ahj.2008.05.016

10. Larsson TE, Olauson H, Hagstrom E, Ingelsson E, Arnlov J, Lind L, Sundstrom J. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol. 2010;30(2):333-9. https://doi.org/10.1161/ATVBAHA.109.196675

11. McGovern AP, de Lusignan S, van Vlymen J, Liyanage H, Tomson CR, Gallagher H, Rafiq M, Jones S. Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study. PLoS One. 2013;8(9):e74996. https://doi.org/10.1371/journal.pone.0074996

12. Lutsey PL, Alonso A, Michos ED, Loehr LR, Astor BC, Coresh J, Folsom AR. Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2014;100(3):756-64. https://doi.org/10.3945/ajcn.114.085167

13. Rohrmann S, Garmo H, Malmstrom H, Hammar N, Jungner I, Walldius G, Van Hemelrijck M. Association between serum calcium concentration and risk of incident and fatal cardiovascular disease in the prospective AMORIS study. Atherosclerosis. 2016;251:85-93. https://doi.org/10.1016/j.atherosclerosis.2016.06.004

14. Reid IR, Gamble GD, Bolland MJ. Circulating calcium concentrations, vascular disease and mortality: a systematic review. J Intern Med. 2016;279(6):524-40. https://doi.org/10.1111/joim.12464

15. Campos-Obando N, Lahousse L, Brusselle G, Stricker BH, Hofman A, Franco OH, Uitterlinden AG, Zillikens MC. Serum phosphate levels are related to all-cause, cardiovascular and COPD mortality in men. Eur J Epidemiol. 2018;33(9):859-871. https://doi.org/10.1007/s10654-018-0407-7

16. Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol. 2010;5 Suppl 1:S23-30. https://doi.org/10.2215/CJN.05910809

17. Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol. 2015;10(7):1257-72. https://doi.org/10.2215/CJN.09750913

18. Moe SM. Calcium Homeostasis in Health and in Kidney Disease. Compr Physiol. 2016;6(4):1781-1800. https://doi.org/10.1002/cphy.c150052

19. Peacock M. Phosphate Metabolism in Health and Disease. Calcif Tissue Int. 2021;108(1):3-15. https://doi.org/10.1007/s00223-020- 00686-3

20. Kobylecki CJ, Nordestgaard BG, Afzal S. Plasma Ionized Calcium and Risk of Cardiovascular Disease: 106 774 Individuals from the Copenhagen General Population Study. Clin Chem. 2021;67(1):265- 275. https://doi.org/10.1093/clinchem/hvaa245

21. Ginsberg C, Houben AJHM, Malhotra R, Berendschot TTJM, Dagnelie PC, Kooman JP, Webers CA, Stehouwer CDA, Ix JH. Serum Phosphate and Microvascular Function in a Population-Based Cohort. Clin J Am Soc Nephrol. 2019;14(11):1626-1633. https://doi.org/10.2215/CJN.02610319

22. Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011;123(2):163-9. https://doi.org/10.1161/CIRCULATIONAHA.110.953653

23. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95(1):1-46. https://doi.org/10.1152/physrev.00012.2014

24. Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 1998;136(3):480-90. https://doi.org/10.1016/s0002-8703(98)70224-8

25. Reffelmann T, Ittermann T, Dorr M, Volzke H, Reinthaler M, Petersmann A, Felix SB. Low serum magnesium concentrations predict cardiovascular and all-cause mortality. Atherosclerosis. 2011;219(1):280-4. https://doi.org/10.1016/j.atherosclerosis.2011.05.038

26. Joosten MM, Gansevoort RT, Mukamal KJ, van der Harst P, Geleijnse JM, Feskens EJ, Navis G, Bakker SJ; PREVEND Study Group. Urinary and plasma magnesium and risk of ischemic heart disease. Am J Clin Nutr. 2013;97(6):1299-306. https://doi.org/10.3945/ajcn.112.054114

27. Qu X, Jin F, Hao Y, Li H, Tang T, Wang H, Yan W, Dai K. Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies. PLoS One. 2013;8(3):e57720. https://doi.org/10.1371/journal.pone.0057720

28. Adebamowo SN, Jimenez MC, Chiuve SE, Spiegelman D, Willett WC, Rexrode KM. Plasma magnesium and risk of ischemic stroke among women. Stroke. 2014;45(10):2881-6. https://doi.org/10.1161/ STROKEAHA.114.005917

29. Kunutsor SK, Khan H, Laukkanen JA. Serum magnesium and risk of new onset heart failure in men: the Kuopio Ischemic Heart Disease Study. Eur J Epidemiol. 2016;31(10):1035-1043. https://doi.org/10.1007/s10654-016-0164-4

30. Kieboom BC, Niemeijer MN, Leening MJ, van den Berg ME, Franco OH, Deckers JW, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death. J Am Heart Assoc. 2016;5(1):e002707. https://doi.org/10.1161/JAHA.115.002707

31. Wannamethee SG, Papacosta O, Lennon L, Whincup PH. Serum magnesium and risk of incident heart failure in older men: The British Regional Heart Study. Eur J Epidemiol. 2018;33(9):873-882. https://doi.org/10.1007/s10654-018-0388-6

32. Rodriguez-Ortiz ME, Gomez-Delgado F, Arenas de Larriva AP, Canalejo A, Gomez-Luna P, Herencia C, Lopez-Moreno J, Rodriguez M, Lopez-Miranda J, Almaden Y. Serum Magnesium is associated with Carotid Atherosclerosis in patients with high cardiovascular risk (CORDIOPREV Study). Sci Rep. 2019;9(1):8013. https://doi.org/10.1038/s41598-019-44322-z

33. Rooney MR, Alonso A, Folsom AR, Michos ED, Rebholz CM, Misialek JR, Chen LY, Dudley S, Lutsey PL. Serum magnesium and the incidence of coronary artery disease over a median 27 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) Study and a meta-analysis. Am J Clin Nutr. 2020;111(1):52-60. https://doi.org/10.1093/ajcn/nqz256

34. Li Q, Chen Q, Zhang H, Xu Z, Wang X, Pang J, Ma J, Ling W, Li D. Associations of serum magnesium levels and calcium-magnesium ratios with mortality in patients with coronary artery disease. Diabetes Metab. 2020;46(5):384-391. https://doi.org/10.1016/j.diabet.2019.12.003

35. Moe SM, Chertow GM, Parfrey PS, Kubo Y, Block GA, CorreaRotter R, Drueke TB, Herzog CA, London GM, Mahaffey KW, Wheeler DC, Stolina M, Dehmel B, Goodman WG, Floege J; Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators. Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation. 2015;132(1):27-39. https://doi.org/10.1161/CIRCULATIONAHA.114.013876

36. Chung M, Tang AM, Fu Z, Wang DD, Newberry SJ. Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis. Ann Intern Med. 2016;165(12):856-866. https://doi.org/10.7326/M16-1165

37. Kahwati LC, Weber RP, Pan H, Gourlay M, LeBlanc E, CokerSchwimmer M, Viswanathan M. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018;319(15):1600-1612. https://doi.org/10.1001/jama.2017.21640

38. Barbarawi M, Kheiri B, Zayed Y, Barbarawi O, Dhillon H, Swaid B, Yelangi A, Sundus S, Bachuwa G, Alkotob ML, Manson JE. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Metaanalysis. JAMA Cardiol. 2019;4(8):765-776. https://doi.org/10.1001/jamacardio.2019.1870

39. Heiss A, Eckert T, Aretz A, Richtering W, van Dorp W, Schafer C, Jahnen-Dechent W. Hierarchical role of fetuin-A and acidic serum proteins in the formation and stabilization of calcium phosphate particles. J Biol Chem. 2008;283(21):14815-25. https://doi.org/10.1074/jbc.M709938200

40. Back M, Aranyi T, Cancela ML, Carracedo M, Conceicao N, Leftheriotis G, Macrae V, Martin L, Nitschke Y, Pasch A, Quaglino D, Rutsch F, Shanahan C, Sorribas V, Szeri F, Valdivielso P, Vanakker O, Kempf H. Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet. Front Cardiovasc Med. 2019;5:196. https://doi.org/10.3389/fcvm.2018.00196

41. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004;95(11):1046-57. https://doi.org/10.1161/01.RES.0000149165.99974.12

42. Yasuda H. Discovery of the RANKL/RANK/OPG system. J Bone Miner Metab. 2021;39(1):2-11. https://doi.org/10.1007/s00774-020- 01175-1

43. Udagawa N, Koide M, Nakamura M, Nakamichi Y, Yamashita T, Uehara S, Kobayashi Y, Furuya Y, Yasuda H, Fukuda C, Tsuda E. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab. 2021;39(1):19-26. https://doi.org/10.1007/s00774-020-01162-6

44. Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM. Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Am J Pathol. 2002;161(6):2035- 46. https://doi.org/10.1016/S0002-9440(10)64482-3

45. Speer MY, McKee MD, Guldberg RE, Liaw L, Yang HY, Tung E, Karsenty G, Giachelli CM. Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med. 2002;196(8):1047-55. https://doi.org/10.1084/jem.20020911

46. Paloian NJ, Leaf EM, Giachelli CM. Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int. 2016;89(5):1027-1036. https://doi.org/10.1016/j.kint.2015.12.046

47. Orriss IR, Arnett TR, Russell RG. Pyrophosphate: a key inhibitor of mineralisation. Curr Opin Pharmacol. 2016;28:57-68. https://doi.org/10.1016/j.coph.2016.03.003

48. Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen-Dechent W. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem. 2003;278(15):13333-41. https://doi.org/10.1074/jbc.M210868200

49. Busch E, Hohenester E, Timpl R, Paulsson M, Maurer P. Calcium affinity, cooperativity, and domain interactions of extracellular EFhands present in BM-40. J Biol Chem. 2000;275(33):25508-15. https://doi.org/10.1074/jbc.M001770200

50. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78-81. https://doi.org/10.1038/386078a0

51. Viegas CS, Rafael MS, Enriquez JL, Teixeira A, Vitorino R, Luis IM, Costa RM, Santos S, Cavaco S, Neves J, Macedo AL, Willems BA, Vermeer C, Simes DC. Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol. 2015;35(2):399-408. https://doi.org/10.1161/ATVBAHA.114.304823

52. Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med. 2013;19(4):217-26. https://doi.org/10.1016/j.molmed.2012.12.008

53. Rafael MS, Cavaco S, Viegas CS, Santos S, Ramos A, Willems BA, Herfs M, Theuwissen E, Vermeer C, Simes DC. Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ-carboxylation status. Mol Nutr Food Res. 2014;58(8):1636-46. https://doi.org/10.1002/mnfr.201300941

54. Tesfamariam B. Involvement of Vitamin K-Dependent Proteins in Vascular Calcification. J Cardiovasc Pharmacol Ther. 2019;24(4):323-333. https://doi.org/10.1177/1074248419838501

55. Shioi A, Morioka T, Shoji T, Emoto M. The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification. Nutrients. 2020;12(2):583. https://doi.org/10.3390/nu12020583

56. Xiao H, Chen J, Duan L, Li S. Role of emerging vitamin K dependent proteins: Growth arrest specific protein 6, Gla rich protein and periostin (Review). Int J Mol Med. 2021;47(3):1. https://doi.org/10.3892/ijmm.2020.4835

57. Heiss A, Pipich V, Jahnen-Dechent W, Schwahn D. Fetuin-A is a mineral carrier protein: small angle neutron scattering provides new insight on Fetuin-A controlled calcification inhibition. Biophys J. 2010;99(12):3986-95. https://doi.org/10.1016/j.bpj.2010.10.030

58. Jahnen-Dechent W, Heiss A, Schafer C, Ketteler M. Fetuin-A regulation of calcified matrix metabolism. Circ Res. 2011;108(12):1494-509. https://doi.org/10.1161/CIRCRESAHA.110.234260

59. Wu CY, Young L, Young D, Martel J, Young JD. Bions: a family of biomimetic mineralo-organic complexes derived from biological fluids. PLoS One. 2013;8(9):e75501. https://doi.org/10.1371/journal.pone.0075501

60. Rochette CN, Rosenfeldt S, Heiss A, Narayanan T, Ballauff M, Jahnen-Dechent W. A shielding topology stabilizes the early stage protein-mineral complexes of fetuin-A and calcium phosphate: a timeresolved small-angle X-ray study. Chembiochem. 2009;10(4):735- 40. https://doi.org/10.1002/cbic.200800719

61. Chen X, Zhang Y, Chen Q, Li Q, Li Y, Ling W. Lower Plasma Fetuin-A Levels Are Associated With a Higher Mortality Risk in Patients With Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2017;37(11):2213-2219. https://doi.org/10.1161/ATVBAHA.117.309700

62. Peng W, Zhang C, Wang Z, Yang W. Prediction of all-cause mortality with hypoalbuminemia in patients with heart failure: a meta-analysis. Biomarkers. 2019;24(7):631-637. https://doi.org/10.1080/135475 0X.2019.1652686

63. Xie WM, Ran LS, Jiang J, Chen YS, Ji HY, Quan XQ. Association between fetuin-A and prognosis of CAD: A systematic review and meta-analysis. Eur J Clin Invest. 2019;49(5):e13091. https://doi. org/10.1111/eci.13091

64. Ronit A, Kirkegaard-Klitbo DM, Dohlmann TL, Lundgren J, Sabin CA, Phillips AN, Nordestgaard BG, Afzal S. Plasma Albumin and Incident Cardiovascular Disease: Results From the CGPS and an Updated Meta-Analysis. Arterioscler Thromb Vasc Biol. 2020;40(2):473-482. https://doi.org/10.1161/ATVBAHA.119.313681

65. Seidu S, Kunutsor SK, Khunti K. Serum albumin, cardiometabolic and other adverse outcomes: systematic review and meta-analyses of 48 published observational cohort studies involving 1,492,237 participants. Scand Cardiovasc J. 2020;54(5):280-293. doi: 10.1080/14017431.2020.1762918

66. Pignatelli P, Farcomeni A, Menichelli D, Pastori D, Violi F. Serum albumin and risk of cardiovascular events in primary and secondary prevention: a systematic review of observational studies and Bayesian meta-regression analysis. Intern Emerg Med. 2020;15(1):135-143. https://doi.org/10.1007/s11739-019-02204-2

67. Pruijm M, Lu Y, Megdiche F, Piskunowicz M, Milani B, Stuber M, Bachtler M, Vogt B, Burnier M, Pasch A. Serum calcification propensity is associated with renal tissue oxygenation and resistive index in patients with arterial hypertension or chronic kidney disease. J Hypertens. 2017;35(10):2044-2052. https://doi.org/10.1097/HJH.0000000000001406

68. Nakazato J, Hoshide S, Wake M, Miura Y, Kuro-O M, Kario K. Association of calciprotein particles measured by a new method with coronary artery plaque in patients with coronary artery disease: A cross-sectional study. J Cardiol. 2019;74(5):428-435. https://doi.org/10.1016/j.jjcc.2019.04.008

69. Кутихин А.Г., Шишкова Д.К., Хрячкова О.Н., Фролов А.В., Шабаев А.Р., Загородников Н.И., Маркова В.Е., Богданов Л.А., Осяев Н.Ю., Индукаева Е.В., Груздева О.В. Закономерности формирования кальций-фосфатных бионов у пациентов с каротидным и коронарным атеросклерозом. Российский кардиологический журнал. 2020;25(12):39-48. https://doi.org/10.15829/1560-4071-2020-3881

70. Eelderink C, Te Velde-Keyzer CA, Frenay AS, Vermeulen EA, Bachtler M, Aghagolzadeh P, van Dijk PR, Gansevoort RT, Vervloet MG, Hillebrands JL, Bakker SJL, van Goor H, Pasch A, de Borst MH; NIGRAM2+ consortium. Serum Calcification Propensity and the Risk of Cardiovascular and All-Cause Mortality in the General Population: The PREVEND Study. Arterioscler Thromb Vasc Biol. 2020;40(8):1942-1951. https://doi.org/10.1161/ATVBAHA.120.314187

71. Keyzer CA, de Borst MH, van den Berg E, Jahnen-Dechent W, Arampatzis S, Farese S, Bergmann IP, Floege J, Navis G, Bakker SJ, van Goor H, Eisenberger U, Pasch A. Calcification Propensity and Survival among Renal Transplant Recipients. J Am Soc Nephrol. 2016;27(1):239-48. https://doi.org/10.1681/ASN.2014070670

72. Dahle DO, Asberg A, Hartmann A, Holdaas H, Bachtler M, Jenssen TG, Dionisi M, Pasch A. Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All-Cause Mortality in Kidney Transplant Recipients. Am J Transplant. 2016;16(1):204-12. https://doi.org/10.1111/ajt.13443

73. Pasch A, Block GA, Bachtler M, Smith ER, Jahnen-Dechent W, Arampatzis S, Chertow GM, Parfrey P, Ma X, Floege J. Blood Calcification Propensity, Cardiovascular Events, and Survival in Patients Receiving Hemodialysis in the EVOLVE Trial. Clin J Am Soc Nephrol. 2017;12(2):315-322. https://doi.org/10.2215/CJN.04720416

74. Bostom A, Pasch A, Madsen T, Roberts MB, Franceschini N, Steubl D, Garimella PS, Ix JH, Tuttle KR, Ivanova A, Shireman T, Gohh R, Merhi B, Jarolim P, Kusek JW, Pfeffer MA, Liu S, Eaton CB. Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients. Am J Nephrol. 2018;48(1):21-31. https://doi.org/10.1159/000491025

75. Bundy JD, Cai X, Scialla JJ, Dobre MA, Chen J, Hsu CY, Leonard MB, Go AS, Rao PS, Lash JP, Townsend RR, Feldman HI, de Boer IH, Block GA, Wolf M, Smith ER, Pasch A, Isakova T; CRIC Study Investigators. Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis. 2019;73(6):806-814. https://doi.org/10.1053/j.ajkd.2019.01.024

76. Bundy JD, Cai X, Mehta RC, Scialla JJ, de Boer IH, Hsu CY, Go AS, Dobre MA, Chen J, Rao PS, Leonard MB, Lash JP, Block GA, Townsend RR, Feldman HI, Smith ER, Pasch A, Isakova T; CRIC Study Investigators. Serum Calcification Propensity and Clinical Events in CKD. Clin J Am Soc Nephrol. 2019;14(11):1562-1571. https://doi.org/10.2215/CJN.04710419

77. Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, Lindblad L, Lewis EF, Drisko J, Lee KL; TACT Investigators. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241-50. https://doi.org/10.1001/jama.2013.2107

78. Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y, Nahin RL, Ouyang P, Rozema T, Magaziner A, Nahas R, Lewis EF, Lindblad L, Lee KL. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014;7(1):15-24. https://doi.org/10.1161/CIRCOUTCOMES.113.000663

79. Ujueta F, Arenas IA, Escolar E, Diaz D, Boineau R, Mark DB, Golden P, Lindblad L, Kim H, Lee KL, Lamas GA. The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT). J Diabetes Complications. 2019;33(7):490-494. https://doi.org/10.1016/j.jdiacomp.2019.04.005

80. Yamada H, Kuro-O M, Ishikawa SE, Funazaki S, Kusaka I, Kakei M, Hara K. Daily variability in serum levels of calciprotein particles and their association with mineral metabolism parameters: A crosssectional pilot study. Nephrology (Carlton). 2018;23(3):226-230. https://doi.org/10.1111/nep.12994

81. Avila MD, Escolar E, Lamas GA. Chelation therapy after the trial to assess chelation therapy: results of a unique trial. Curr Opin Cardiol. 2014;29(5):481-8. https://doi.org/10.1097/HCO.0000000000000096

82. Quinones H, Hamdi T, Sakhaee K, Pasch A, Moe OW, Pak CYC. Control of metabolic predisposition to cardiovascular complications of chronic kidney disease by effervescent calcium magnesium citrate: a feasibility study. J Nephrol. 2019;32(1):93-100. https://doi.org/10.1007/s40620-018-0559-2

83. Bressendorff I, Hansen D, Schou M, Silver B, Pasch A, Bouchelouche P, Pedersen L, Rasmussen LM, Brandi L. Oral Magnesium Supplementation in Chronic Kidney Disease Stages 3 and 4: Efficacy, Safety, and Effect on Serum Calcification Propensity-A Prospective Randomized Double-Blinded Placebo-Controlled Clinical Trial. Kidney Int Rep. 2016;2(3):380-389. https://doi.org/10.1016/j. ekir.2016.12.008

84. Thiem U, Soellradl I, Robl B, Watorek E, Blum S, Dumfarth A, Marculescu R, Pasch A, Haller MC, Cejka D. The effect of phosphate binder therapy with sucroferric oxyhydroxide on calcification propensity in chronic haemodialysis patients: a randomized, controlled, crossover trial. Clin Kidney J. 2020;14(2):631-638. https://doi.org/10.1093/ckj/sfaa154

85. Smith ER, Pan FFM, Hewitson TD, Toussaint ND, Holt SG. Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial. Kidney Int Rep. 2020;5(9):1432-1447. https://doi.org/10.1016/j.ekir.2020.06.014

86. Pasch A, Farese S, Graber S, Wald J, Richtering W, Floege J, JahnenDechent W. Nanoparticle-based test measures overall propensity for calcification in serum. J Am Soc Nephrol. 2012;23(10):1744-52. https://doi.org/10.1681/ASN.2012030240

87. Shishkova D, Markova V, Sinitsky M, Tsepokina A, Velikanova E, Bogdanov L, Glushkova T, Kutikhin A. Calciprotein Particles Cause Endothelial Dysfunction under Flow. Int J Mol Sci. 2020;21(22):8802. https://doi.org/10.3390/ijms21228802

88. Smith ER, Hewitson TD, Cai MMX, Aghagolzadeh P, Bachtler M, Pasch A, Holt SG. A novel fluorescent probe-based flow cytometric assay for mineral-containing nanoparticles in serum. Sci Rep. 2017;7(1):5686. https://doi.org/10.1038/s41598-017-05474-y

89. Ruderman I, Smith ER, Toussaint ND, Hewitson TD, Holt SG. Longitudinal changes in bone and mineral metabolism after cessation of cinacalcet in dialysis patients with secondary hyperparathyroidism. BMC Nephrol. 2018;19(1):113. https://doi.org/10.1186/s12882-018- 0910-9

90. Cai MMX, Smith ER, Kent A, Huang L, Hewitson TD, McMahon LP, Holt SG. Calciprotein Particle Formation in Peritoneal Dialysis Effluent Is Dependent on Dialysate Calcium Concentration. Perit Dial Int. 2018;38(4):286-292. https://doi.org/10.3747/pdi.2017.00163

91. Bressendorff I, Hansen D, Pasch A, Holt SG, Schou M, Brandi L, Smith ER. The effect of increasing dialysate magnesium on calciprotein particles, inflammation and bone markers: post hoc analysis from a randomized controlled clinical trial. Nephrol Dial Transplant. 2019;gfz234. https://doi.org/10.1093/ndt/gfz234

92. Kutikhin AG, Velikanova EA, Mukhamadiyarov RA, Glushkova TV, Borisov VV, Matveeva VG, Antonova LV, Filip'ev DE, Golovkin AS, Shishkova DK, Burago AY, Frolov AV, Dolgov VY, Efimova OS, Popova AN, Malysheva VY, Vladimirov AA, Sozinov SA, Ismagilov ZR, Russakov DM, Lomzov AA, Pyshnyi DV, Gutakovsky AK, Zhivodkov YA, Demidov EA, Peltek SE, Dolganyuk VF, Babich OO, Grigoriev EV, Brusina EB, Barbarash OL, Yuzhalin AE. Apoptosismediated endothelial toxicity but not direct calcification or functional changes in anti-calcification proteins defines pathogenic effects of calcium phosphate bions. Sci Rep. 2016;6:27255. https://doi.org/10.1038/srep27255

93. Koppert S, Buscher A, Babler A, Ghallab A, Buhl EM, Latz E, Hengstler JG, Smith ER, Jahnen-Dechent W. Cellular Clearance and Biological Activity of Calciprotein Particles Depend on Their Maturation State and Crystallinity. Front Immunol. 2018;9:1991. https://doi.org/10.3389/fimmu.2018.01991

94. Shishkova D, Velikanova E, Sinitsky M, Tsepokina A, Gruzdeva O, Bogdanov L, Kutikhin A. Calcium Phosphate Bions Cause Intimal Hyperplasia in Intact Aortas of Normolipidemic Rats through Endothelial Injury. Int J Mol Sci. 2019;20(22):5728. https://doi.org/10.3390/ijms20225728

95. Gimbrone MA Jr, Garcia-Cardena G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016;118(4):620- 636. https://doi.org/10.1161/CIRCRESAHA.115.306301

96. Jensen HA, Mehta JL. Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis. Expert Rev Cardiovasc Ther. 2016;14(9):1021-33. https://doi.org/10.1080/14779072.2016.1207527

97. Cahill PA, Redmond EM. Vascular endothelium - Gatekeeper of vessel health. Atherosclerosis. 2016;248:97-109. https://doi.org/10.1016/j.atherosclerosis.2016.03.007

98. Aghagolzadeh P, Bachtler M, Bijarnia R, Jackson C, Smith ER, Odermatt A, Radpour R, Pasch A. Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α. Atherosclerosis. 2016;251:404-414. https://doi.org/10.1016/j.atherosclerosis.2016.05.044.

99. Aghagolzadeh P, Radpour R, Bachtler M, van Goor H, Smith ER, Lister A, Odermatt A, Feelisch M, Pasch A. Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/ NRF2/NQO1 activation. Atherosclerosis. 2017;265:78-86. https://doi.org/10.1016/j.atherosclerosis.2017.08.012.

100. Viegas CSB, Santos L, Macedo AL, Matos AA, Silva AP, Neves PL, Staes A, Gevaert K, Morais R, Vermeer C, Schurgers L, Simes DC. Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification: A Role for GRP (Gla-Rich Protein). Arterioscler Thromb Vasc Biol. 2018;38(3):575- 587. https://doi.org/10.1161/ATVBAHA.117.310578

101. Шишкова Д.К., Великанова Е.А., Кривкина Е.О., Миронов А.В., Кудрявцева Ю.А., Кутихин А.Г. Токсическое действие кальций-фосфатных бионов на адвентицию брюшной аорты крыс. Атеросклероз и дислипидемии. 2018;32(3):37-43.

102. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14(6):392- 404. https://doi.org/10.1038/nri3671

103. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41(1):21-35. https://doi.org/10.1016/j.immuni.2014.06.013

104. Gasteiger G, Rudensky AY. Interactions between innate and adaptive lymphocytes. Nat Rev Immunol. 2014;14(9):631-9. https://doi.org/10.1038/nri3726

105. Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization. Annu Rev Immunol. 2015;33:643-75. https://doi.org/10.1146/annurev-immunol-032414-112220

106. Nicholson LB. The immune system. Essays Biochem. 2016;60(3):275- 301. https://doi.org/10.1042/EBC20160017 107.

107. Silvestre-Roig C, Braster Q, Ortega-Gomez A, Soehnlein O. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol. 2020;17(6):327-340. https://doi.org/10.1038/s41569-019-0326-7

108. Nemeth T, Sperandio M, Mocsai A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov. 2020;19(4):253-275. https://doi.org/10.1038/s41573-019-0054-z

109. Schloss MJ, Swirski FK, Nahrendorf M. Modifiable Cardiovascular Risk, Hematopoiesis, and Innate Immunity. Circ Res. 2020;126(9):1242-1259. https://doi.org/10.1161/CIRCRESAHA.120.315936

110. Poller WC, Nahrendorf M, Swirski FK. Hematopoiesis and Cardiovascular Disease. Circ Res. 2020;126(8):1061-1085. doi: 10.1161/CIRCRESAHA.120.315895.

111. Herrmann M, Schafer C, Heiss A, Graber S, Kinkeldey A, Buscher A, Schmitt MM, Bornemann J, Nimmerjahn F, Herrmann M, Helming L, Gordon S, Jahnen-Dechent W. Clearance of fetuinA--containing calciprotein particles is mediated by scavenger receptor-A. Circ Res. 2012;111(5):575-84. https://doi.org/10.1161/CIRCRESAHA.111.261479

112. Hyun YM, Lefort CT, Kim M. Leukocyte integrins and their ligand interactions. Immunol Res. 2009;45(2-3):195-208. https://doi.org/10.1007/s12026-009-8101-1

113. McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res. 2015;107(3):331-9. https://doi.org/10.1093/cvr/cvv154

114. Allen S, Moran N. Cell Adhesion Molecules: Therapeutic Targets for Inhibition of Inflammatory States. Semin Thromb Hemost. 2015;41(6):563-71. https://doi.org/10.1055/s-0035-1556588

115. Dustin ML. Integrins and Their Role in Immune Cell Adhesion. Cell. 2019;177(3):499-501. https://doi.org/10.1016/j.cell.2019.03.038

116. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279-287. https://doi.org/10.1038/nm.4294

117. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134-147. https://doi.org/10.1038/nri.2017.105

118. Thalin C, Hisada Y, Lundstrom S, Mackman N, Wallen H. Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(9):1724-1738. https://doi.org/10.1161/ATVBAHA.119.312463

119. Doring Y, Libby P, Soehnlein O. Neutrophil Extracellular Traps Participate in Cardiovascular Diseases: Recent Experimental and Clinical Insights. Circ Res. 2020;126(9):1228-1241. https://doi. org/10.1161/CIRCRESAHA.120.315931

120. Castanheira FVS, Kubes P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood. 2019;133(20):2178-2185. https://doi.org/10.1182/blood-2018-11-844530

121. Jimenez-Alcazar M, Rangaswamy C, Panda R, Bitterling J, Simsek YJ, Long AT, Bilyy R, Krenn V, Renne C, Renne T, Kluge S, Panzer U, Mizuta R, Mannherz HG, Kitamura D, Herrmann M, Napirei M, Fuchs TA. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science. 2017;358(6367):1202-1206. https://doi.org/10.1126/science.aam8897

122. Franck G, Mawson TL, Folco EJ, Molinaro R, Ruvkun V, Engelbertsen D, Liu X, Tesmenitsky Y, Shvartz E, Sukhova GK, Michel JB, Nicoletti A, Lichtman A, Wagner D, Croce KJ, Libby P. Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion. Circ Res. 2018;123(1):33-42. https://doi.org/10.1161/CIRCRESAHA.117.312494

123. Becker RC, Sexton T, Smyth SS. Translational Implications of Platelets as Vascular First Responders. Circ Res. 2018;122(3):506- 522. https://doi.org/10.1161/CIRCRESAHA.117.310939

124. van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol. 2019;16(3):166-179. https://doi.org/10.1038/s41569-018-0110-0

125. Aslan JE. Platelet Proteomes, Pathways, and Phenotypes as Informants of Vascular Wellness and Disease. Arterioscler Thromb Vasc Biol. 2021;41(3):999-1011. https://doi.org/10.1161/ATVBAHA.120.314647

126. Duvernay MT, Temple KJ, Maeng JG, Blobaum AL, Stauffer SR, Lindsley CW, Hamm HE. Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets. Mol Pharmacol. 2017;91(1):39-47. https://doi.org/10.1124/mol.116.106666

127. Rossaint J, Margraf A, Zarbock A. Role of Platelets in Leukocyte Recruitment and Resolution of Inflammation. Front Immunol. 2018;9:2712. https://doi.org/10.3389/fimmu.2018.02712

128. Lin YC, Ko YC, Hung SC, Lin YT, Lee JH, Tsai JY, Kung PH, Tsai MC, Chen YF, Wu CC. Selective Inhibition of PAR4 (ProteaseActivated Receptor 4)-Mediated Platelet Activation by a Synthetic Nonanticoagulant Heparin Analog. Arterioscler Thromb Vasc Biol. 2019;39(4):694-703. https://doi.org/10.1161/ATVBAHA.118.311758

129. Puhm F, Boilard E, Machlus KR. Platelet Extracellular Vesicles: Beyond the Blood. Arterioscler Thromb Vasc Biol. 2021;41(1):87- 96. https://doi.org/10.1161/ATVBAHA.120.314644

130. Flaumenhaft R, Dilks JR, Richardson J, Alden E, Patel-Hett SR, Battinelli E, Klement GL, Sola-Visner M, Italiano JE Jr. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood. 2009;113(5):1112-21. https://doi.org/10.1182/blood-2008-06-163832

131. Arraud N, Linares R, Tan S, Gounou C, Pasquet JM, Mornet S, Brisson AR. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014;12(5):614-27. https://doi.org/10.1111/jth.12554

132. Aatonen MT, Ohman T, Nyman TA, Laitinen S, Gronholm M, Siljander PR. Isolation and characterization of platelet-derived extracellular vesicles. J Extracell Vesicles. 2014;3:24692. https://doi.org/10.3402/jev.v3.24692

133. French SL, Butov KR, Allaeys I, Canas J, Morad G, Davenport P, Laroche A, Trubina NM, Italiano JE, Moses MA, Sola-Visner M, Boilard E, Panteleev MA, Machlus KR. Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation. Blood Adv. 2020;4(13):3011-3023. https://doi.org/10.1182/bloodadvances.2020001758

134. Milioli M, Ibanez-Vea M, Sidoli S, Palmisano G, Careri M, Larsen MR. Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists. J Proteomics. 2015;121:56-66. https://doi.org/10.1016/j.jprot.2015.03.013

135. Nomura S, Uehata S, Saito S, Osumi K, Ozeki Y, Kimura Y. Enzyme immunoassay detection of platelet-derived microparticles and RANTES in acute coronary syndrome. Thromb Haemost. 2003;89(3):506-12.

136. Chiva-Blanch G, Laake K, Myhre P, Bratseth V, Arnesen H, Solheim S, Badimon L, Seljeflot I. Platelet-, monocyte-derived and tissue factor-carrying circulating microparticles are related to acute myocardial infarction severity. PLoS One. 2017;12(2):e0172558. https://doi.org/10.1371/journal.pone.0172558

137. Varga-Szabo D, Braun A, Nieswandt B. Calcium signaling in platelets. J Thromb Haemost. 2009;7(7):1057-66. https://doi.org/10.1111/j.1538-7836.2009.03455.x

138. Li Z, Delaney MK, O'Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol. 2010;30(12):2341-9. https://doi.org/10.1161/ATVBAHA.110.207522

139. Boulanger CM, Loyer X, Rautou PE, Amabile N. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol. 2017;14(5):259- 272. https://doi.org/10.1038/nrcardio.2017.7

140. Ridger VC, Boulanger CM, Angelillo-Scherrer A, Badimon L, BlancBrude O, Bochaton-Piallat ML, Boilard E, Buzas EI, Caporali A, Dignat-George F, Evans PC, Lacroix R, Lutgens E, Ketelhuth DFJ, Nieuwland R, Toti F, Tunon J, Weber C, Hoefer IE. Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. Thromb Haemost. 2017;117(7):1296-1316. https://doi.org/10.1160/TH16-12-0943

141. Kuo WP, Tigges JC, Toxavidis V, Ghiran I. Red Blood Cells: A Source of Extracellular Vesicles. Methods Mol Biol. 2017;1660:15- 22. https://doi.org/10.1007/978-1-4939-7253-1_2

142. Thangaraju K, Neerukonda SN, Katneni U, Buehler PW. Extracellular Vesicles from Red Blood Cells and Their Evolving Roles in Health, Coagulopathy and Therapy. Int J Mol Sci. 2020;22(1):153. https://doi.org/10.3390/ijms22010153

143. Pernow J, Mahdi A, Yang J, Zhou Z. Red blood cell dysfunction: a new player in cardiovascular disease. Cardiovasc Res. 2019;115(11):1596-1605. https://doi.org/10.1093/cvr/cvz156

144. Pretorius E, du Plooy JN, Bester J. A Comprehensive Review on Eryptosis. Cell Physiol Biochem. 2016;39(5):1977-2000. https://doi.org/10.1159/000447895

145. Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: A paradigm shift towards understanding the (patho) physiological implications of programmed cell death of erythrocytes. Blood Rev. 2017;31(6):349-361. https://doi.org/10.1016/j.blre.2017.06.001

146. Bonan NB, Steiner TM, Kuntsevich V, Virzi GM, Azevedo M, Nakao LS, Barreto FC, Ronco C, Thijssen S, Kotanko P, PecoitsFilho R, Moreno-Amaral AN. Uremic Toxicity-Induced Eryptosis and Monocyte Modulation: The Erythrophagocytosis as a Novel Pathway to Renal Anemia. Blood Purif. 2016;41(4):317-23. https://doi.org/10.1159/000443784

147. Tozoni SS, Dias GF, Bohnen G, Grobe N, Pecoits-Filho R, Kotanko P, Moreno-Amaral AN. Uremia and Hypoxia Independently Induce Eryptosis and Erythrocyte Redox Imbalance. Cell Physiol Biochem. 2019;53:794-804. https://doi.org/10.33594/000000173

148. Zhou Z, Mahdi A, Tratsiakovich Y, Zahoran S, Kovamees O, Nordin F, Uribe Gonzalez AE, Alvarsson M, Ostenson CG, Andersson DC, Hedin U, Hermesz E, Lundberg JO, Yang J, Pernow J. Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I. J Am Coll Cardiol. 2018;72(7):769-780. https://doi. org/10.1016/j.jacc.2018.05.052

149. Yang J, Zheng X, Mahdi A, Zhou Z, Tratsiakovich Y, Jiao T, Kiss A, Kovamees O, Alvarsson M, Catrina SB, Lundberg JO, Brismar K, Pernow J. Red Blood Cells in Type 2 Diabetes Impair Cardiac PostIschemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species. JACC Basic Transl Sci. 2018;3(4):450-463. https://doi.org/10.1016/j.jacbts.2018.03.006

150. Yang J, Gonon AT, Sjoquist PO, Lundberg JO, Pernow J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci U S A. 2013;110(37):15049-54. https://doi.org/10.1073/pnas.1307058110

151. Bor-Kucukatay M, Yalcin O, Gokalp O, Kipmen-Korgun D, Yesilkaya A, Baykal A, Ispir M, Senturk UK, Kaputlu I, Baskurt OK. Red blood cell rheological alterations in hypertension induced by chronic inhibition of nitric oxide synthesis in rats. Clin Hemorheol Microcirc. 2000;22(4):267-75.

152. Merx MW, Gorressen S, van de Sandt AM, Cortese-Krott MM, Ohlig J, Stern M, Rassaf T, Godecke A, Gladwin MT, Kelm M. Depletion of circulating blood NOS3 increases severity of myocardial infarction and left ventricular dysfunction. Basic Res Cardiol. 2014;109(1):398. https://doi.org/10.1007/s00395-013-0398-1

153. Diederich L, Suvorava T, Sansone R, Keller TCS 4th, Barbarino F, Sutton TR, Kramer CM, Luckstadt W, Isakson BE, Gohlke H, Feelisch M, Kelm M, Cortese-Krott MM. On the Effects of Reactive Oxygen Species and Nitric Oxide on Red Blood Cell Deformability. Front Physiol. 2018;9:332. https://doi.org/10.3389/fphys.2018.00332

154. Simmonds MJ, Detterich JA, Connes P. Nitric oxide, vasodilation and the red blood cell. Biorheology. 2014;51(2-3):121-34. https://doi.org/10.3233/BIR-140653

155. McMahon TJ. Red Blood Cell Deformability, Vasoactive Mediators, and Adhesion. Front Physiol. 2019;10:1417. https://doi.org/10.3389/fphys.2019.01417

156. Gyawali P, Richards RS, Uba Nwose E. Erythrocyte morphology in metabolic syndrome. Expert Rev Hematol. 2012;5(5):523-31. https://doi.org/10.1586/ehm.12.47

157. Belanger AM, Keggi C, Kanias T, Gladwin MT, Kim-Shapiro DB. Effects of nitric oxide and its congeners on sickle red blood cell deformability. Transfusion. 2015;55(10):2464-72. https://doi.org/10.1111/trf.13134

158. Gallagher PG. Disorders of erythrocyte hydration. Blood. 2017;130(25):2699-2708. https://doi.org/10.1182/blood-2017-04-590810

159. Caulier A, Rapetti-Mauss R, Guizouarn H, Picard V, Garcon L, Badens C. Primary red cell hydration disorders: Pathogenesis and diagnosis. Int J Lab Hematol. 2018;40 Suppl 1:68-73. https://doi.org/10.1111/ijlh.12820

160. Кутихин А.Г., Шишкова Д.К., Мухамадияров Р.А., Великанова Е.А. Детекция окислительного стресса в артериальных эндотелиальных клетках человека при воздействии кальций-фосфатных бионов. Патологическая физиология и экспериментальная терапия. 2021; 65(1): 70-78. https://doi.org/10.25557/0031-2991.2021.01.70-78.