aterosklerozАтеросклерозAteroscleroz2078-256X2949-3633НИИТПМ-филиал ИЦиГ СО РАН10.52727/2078-256X-2021-17-2-72-82ateroskleroz-438Research ArticleОБЗОРЫREVIEWSБиомаркеры кальцификации, их связь с заболеваниями сердечно-сосудистой системы и значение в клинической практикеBiomarkers of vascular calcification: their relationship with diseases of the cardiovascular system and their importance in clinical practiceМаслацовН. А.MaslatsovN. A.

 аспирант, младший научный сотрудник

 630089, Новосибирск, ул. Бориса Богаткова, 175/1 

 630089, Novosibirsk, Boris Bogatkov str., 175/1 

maslatsoff@mail.ruhttps://orcid.org/0000-0002-4936-8362РагиноЮ. И.RaginoYu. I.

 д-р мед. наук, проф., чл.-корр. РАН, руководитель 

 630089, Новосибирск, ул. Бориса Богаткова, 175/1 

 630089, Novosibirsk, Boris Bogatkov str., 175/1 

НИИ терапии и профилактической медицины – филиал ФГБНУ ФИЦ Институт цитологии и генетики СО РАНРоссияResearch Institute of Internal and Preventive Medicine – Branch of Federal Research Center Institute of Cytology and Genetics of SB RASRussian Federation2021100820211727282Copyright © Маслацов Н.А., Рагино Ю.И., 20212021Маслацов Н.А., Рагино Ю.И.Maslatsov N.A., Ragino Y.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://ateroskleroz.elpub.ru/jour/article/view/438

 Данный литературный обзор посвящен актуальным проблемам сосудистой кальцификации с акцентом на связи  некоторых биохимических маркеров сосудистой  кальцификации (в приоритете остеопротегерин и остеопонтин) с сердечно-сосудистыми заболеваниями и другими ассоциированными состояниями. Также многие  аспекты нижеприведенных исследований имеют  непосредственно прикладной, клинический характер, а  некоторые положения помогают внести ясность в патофизиологию сосудистой кальцификации. Цель настоящего обзора – обобщение и систематизация актуальных знаний о вкладе биохимических маркеров сосудистой кальцификации в патологические процессы,  происходящие в сосудистой стенке и приводящие в конечном итоге сосудистого континуума к сердечно-сосудистым событиям. В обзоре представлены самые современные данные отечественных и зарубежных исследований, посвящённые сосудистой кальцификации. Для его подготовки использованы базы данных PubMed, Google Scholar, ScienceDirect, MDPI, Hindawi, Oxford  Academic. 

 The literature review highlights the results of the most recent foreign and Russian studies on topical problems of vascular calcification with an emphasis on the relationship between some biochemical markers of vascular calcification (in priority osteoprotegerin and osteopontin) with cardiovascular disease and other associated conditions. Including some provisions of the reviewed studies help to clarify the pathophysiology mechanisms of vascular calcification. And it should also be noted that many aspects of the reviewed studies are directly related to a clinical practice. The purpose of this review is to generalize and systematize current knowledge about the contribution of vascular calcification biochemical markers to vascular tunic pathology, which finally leads to  cardiovascular events. To prepare it, the databases PubMed, Google Scholar, ScienceDirect, MDPI, Hindawi, Oxford Academic were used. 

сосудистая кальцификацияатеросклеротическая бляшкапотенциальные биомаркерыостеопротегериностеопонтиностеонектиностеокальцинvascular calcificationatherosclerotic plaquepotential biomarkersosteoprotegerinosteopontinosteonectinosteocalcinReferencesKim M., Lee S.P., Kwak S., Yang S., Kim Y.G., Andreini D., Al-Mallah M.H., Budoff M.J., Cademartiri F., Chinnaiyan K., Choi J.H., Conte E., Marques H., Gonçalves P.A., Gottlieb I., Hadamitzky M., Leipsic J.A., Maffei E., Pontone G., Raff G.L., Shin S., Lee B.K., Chun E.J., Sung J.M., Lee S.E., Berman D.S., Lin F.Y., Virmani R., Samady H., Stone P.H., Narula J., Bax J.J., Shaw L.J., Min J.K., Chang H.J. Impact of age on coronary artery plaque progression and clinical outcome: A PARADIGM substudy. J. Cardiovasc. Computed Tomography, 2020; 15 (3): 232–239. doi: 10.1016/j.jcct.2020.09.009Kim M., Lee S.P., Kwak S., Yang S., Kim Y.G., Andreini D., Al-Mallah M.H., Budoff M.J., Cademartiri F., Chinnaiyan K., Choi J.H., Conte E., Marques H., Gonçalves P.A., Gottlieb I., Hadamitzky M., Leipsic J.A., Maffei E., Pontone G., Raff G.L., Shin S., Lee B.K., Chun E.J., Sung J.M., Lee S.E., Berman D.S., Lin F.Y., Virmani R., Samady H., Stone P.H., Narula J., Bax J.J., Shaw L.J., Min J.K., Chang H.J. Impact of age on coronary artery plaque progression and clinical outcome: A PARADIGM substudy. J. Cardiovasc. Computed Tomography, 2020; 15 (3): 232–239. doi: 10.1016/j.jcct.2020.09.009Nicoll R., Henein M. Arterial calcification: A new perspective? Inter. J. Cardiol., 2017; 228: 11–22. doi: 10.1016/j.ijcard.2016.11.099Nicoll R., Henein M. Arterial calcification: A new perspective? Inter. J. Cardiol., 2017; 228: 11–22. doi: 10.1016/j.ijcard.2016.11.099Sánchez-Duffhues G., García de Vinuesa A., van de Pol V., Geerts M.E., de Vries M.R., Janson S. GT, van Dam H., Lindeman J.H., Goumans M.J., ten Dijke P. Inflammation induces endothelial-tomesenchymal transition and promotes vascular calcification through downregulation of BMPR2. J. Pathol., 2019; 247 (3): 333–346. doi: 10.1002/path.5193Sánchez-Duffhues G., García de Vinuesa A., van de Pol V., Geerts M.E., de Vries M.R., Janson S. GT, van Dam H., Lindeman J.H., Goumans M.J., ten Dijke P. Inflammation induces endothelial-tomesenchymal transition and promotes vascular calcification through downregulation of BMPR2. J. Pathol., 2019; 247 (3): 333–346. doi: 10.1002/path.5193Phadwal K., Feng D., Zhu D., MacRae V.E. Autophagy as a novel therapeutic target in vascular calcification. Pharmacol. Ther., 2020; 206: 107430. doi: 10.1016/j.pharmthera.2019.107430Phadwal K., Feng D., Zhu D., MacRae V.E. Autophagy as a novel therapeutic target in vascular calcification. Pharmacol. Ther., 2020; 206: 107430. doi: 10.1016/j.pharmthera.2019.107430Zaker B., Ardalan M. Vascular calcification; Stony bridge between kidney and heart. J. Cardiovasc. Thorac. Res. 2020; 12 (3): 165–171. doi: 10.34172/jcvtr.2020.29Zaker B., Ardalan M. Vascular calcification; Stony bridge between kidney and heart. J. Cardiovasc. Thorac. Res. 2020; 12 (3): 165–171. doi: 10.34172/jcvtr.2020.29Jaminon A., Reesink K., Kroon A., Schurgers L. The Role of Vascular Smooth Muscle Cells in Arterial Remodeling: Focus on Calcification-Related Processes. Int. J. Mol. Sci., 2019; 20 (22): 5694. doi: 10.3390/ijms20225694Jaminon A., Reesink K., Kroon A., Schurgers L. The Role of Vascular Smooth Muscle Cells in Arterial Remodeling: Focus on Calcification-Related Processes. Int. J. Mol. Sci., 2019; 20 (22): 5694. doi: 10.3390/ijms20225694van Rosendael A.R., Cainzos-Achirica M., Al-Mallah M.H. Calcified plaque morphology, density, and risk. Atherosclerosis, 2020; 311: 100–102. doi: 10.1016/j.atherosclerosis.2020.08.022van Rosendael A.R., Cainzos-Achirica M., Al-Mallah M.H. Calcified plaque morphology, density, and risk. Atherosclerosis, 2020; 311: 100–102. doi: 10.1016/j.atherosclerosis.2020.08.022Strauss H.W., Nakahara T., Narula N., Narula J. Vascular Calcification: The Evolving Relationship of Vascular Calcification to Major Acute Coronary Events. J. Nuclear Medicine, 2019; 60 (9): 1207–1212. doi: 10.2967/jnumed.119.230276Strauss H.W., Nakahara T., Narula N., Narula J. Vascular Calcification: The Evolving Relationship of Vascular Calcification to Major Acute Coronary Events. J. Nuclear Medicine, 2019; 60 (9): 1207–1212. doi: 10.2967/jnumed.119.230276Yang T., Guo L., Chen L., Li J., Li Q., Pi Y., Zhu J., Zhang L. A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification. Cell Calcium., 2020; 91: 102265. doi: 10.1016/j.ceca.2020.102265Yang T., Guo L., Chen L., Li J., Li Q., Pi Y., Zhu J., Zhang L. A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification. Cell Calcium., 2020; 91: 102265. doi: 10.1016/j.ceca.2020.102265Hortells L., Sur S., St. Hilaire C. Cell Phenotype Transitions in Cardiovascular Calcification. Front. Cardiovasc. Med., 2018; 5 (27): 1–9. doi: 10.3389/fcvm.2018.00027Hortells L., Sur S., St. Hilaire C. Cell Phenotype Transitions in Cardiovascular Calcification. Front. Cardiovasc. Med., 2018; 5 (27): 1–9. doi: 10.3389/fcvm.2018.00027Danial J.S.H., Murad F., Saez A.J.G., Moawad M.R., Urrico G.S., Vancheri F., Henein M.Y. Computed Histological Quantification of Atherosclerotic Plaque Microcalcifications. Angiology, 2020; 71 (10): 916–919. doi: 10.1177/0003319720939466Danial J.S.H., Murad F., Saez A.J.G., Moawad M.R., Urrico G.S., Vancheri F., Henein M.Y. Computed Histological Quantification of Atherosclerotic Plaque Microcalcifications. Angiology, 2020; 71 (10): 916–919. doi: 10.1177/0003319720939466Jinnouchi H., Sato Y., Sakamoto A., Cornelissen A., Mori M., Kawakami R., Gadhoke N.V., Kolodgie F.D., Virmani R., Finn A.V. Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability. Atherosclerosis, 2020; 306: 85–95. doi: 10.1016/j.atherosclerosis.2020.05.017Jinnouchi H., Sato Y., Sakamoto A., Cornelissen A., Mori M., Kawakami R., Gadhoke N.V., Kolodgie F.D., Virmani R., Finn A.V. Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability. Atherosclerosis, 2020; 306: 85–95. doi: 10.1016/j.atherosclerosis.2020.05.017Pugliese L., Spiritigliozzi L., di Tosto F., Ricci F., Cavallo A.U., di Donna C., de Stasio V., Presicce M., Benelli L., D’Errico F., Pasqualetto M., Floris R., Chiocchi M. Association of plaque calcification pattern and attenuation with instability features and coronary stenosis and calcification grade. Atherosclerosis, 2020; 311: 150–157. doi: 10.1016/j.atherosclerosis.2020.06.021Pugliese L., Spiritigliozzi L., di Tosto F., Ricci F., Cavallo A.U., di Donna C., de Stasio V., Presicce M., Benelli L., D’Errico F., Pasqualetto M., Floris R., Chiocchi M. Association of plaque calcification pattern and attenuation with instability features and coronary stenosis and calcification grade. Atherosclerosis, 2020; 311: 150–157. doi: 10.1016/j.atherosclerosis.2020.06.021Healy A., Berus J.M., Christensen J.L., Lee С., Mantsounga C., Dong W., Watts Jr.J.P., Assali M., Ceneri N., Nilson R., Neverson J., Wu W.C., Choudhary G., Morrison A.R. Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification. Arteriosclerosis, Thrombosis, and Vascular Biology, 2020; 40: 714–732. doi: 10.1161/ATVBAHA.119.313832Healy A., Berus J.M., Christensen J.L., Lee С., Mantsounga C., Dong W., Watts Jr.J.P., Assali M., Ceneri N., Nilson R., Neverson J., Wu W.C., Choudhary G., Morrison A.R. Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification. Arteriosclerosis, Thrombosis, and Vascular Biology, 2020; 40: 714–732. doi: 10.1161/ATVBAHA.119.313832Huang X., D’Addabbo J., Nguyen P.K. Coronary artery calcification: More than meets the eye. J. Nucl. Cardiol., 2020; 1071–3581. doi: 10.1007/s12350-020-02058-8Huang X., D’Addabbo J., Nguyen P.K. Coronary artery calcification: More than meets the eye. J. Nucl. Cardiol., 2020; 1071–3581. doi: 10.1007/s12350-020-02058-8Gijsen F.J.H., Vis B., Barrett H.E., Zadpoor A., Verhagen H.J., Bos D., van der Steen A.F.W., Akyildiz A.C. Morphometric and Mechanical Analyses of Calcifications and Fibrous Plaque Tissue in Carotid Arteries for Plaque Rupture Risk Assessment. IEEE Trans Biomed Eng., 2020; 68 (4): 1429–1438. doi: 10.1109/TBME.2020.3038038Gijsen F.J.H., Vis B., Barrett H.E., Zadpoor A., Verhagen H.J., Bos D., van der Steen A.F.W., Akyildiz A.C. Morphometric and Mechanical Analyses of Calcifications and Fibrous Plaque Tissue in Carotid Arteries for Plaque Rupture Risk Assessment. IEEE Trans Biomed Eng., 2020; 68 (4): 1429–1438. doi: 10.1109/TBME.2020.3038038Kan Y., He W., Ning B., Li H., Wei S., Yu T. The correlation between calcification in carotid plaque and stroke: calcification may be a risk factor for stroke. Int. J. Clin. Exp. Pathol., 2019; 12 (3): 750–758.Kan Y., He W., Ning B., Li H., Wei S., Yu T. The correlation between calcification in carotid plaque and stroke: calcification may be a risk factor for stroke. Int. J. Clin. Exp. Pathol., 2019; 12 (3): 750–758.Pugliese L., Spiritigliozzi L., di Tosto F., Ricci F., Cavallo A.U., di Donna C., de Stasio V., Presicce M., Benelli L., D’Errico F., Pasqualetto M., Floris R., Chiocchi C. Association of plaque calcification pattern and attenuation with instability features and coronary stenosis and calcification grade. Atherosclerosis, 2020; 311: 150–157. doi: 10.1016/j.atherosclerosis.2020.06.021Pugliese L., Spiritigliozzi L., di Tosto F., Ricci F., Cavallo A.U., di Donna C., de Stasio V., Presicce M., Benelli L., D’Errico F., Pasqualetto M., Floris R., Chiocchi C. Association of plaque calcification pattern and attenuation with instability features and coronary stenosis and calcification grade. Atherosclerosis, 2020; 311: 150–157. doi: 10.1016/j.atherosclerosis.2020.06.021Lee S.J., Lee I.K., Jeon J.H. Vascular Calcification – New Insights into Its Mechanism. Int. J. Mol. Sci., 2020; 21 (8): 2685. doi: 10.3390/ijms21082685Lee S.J., Lee I.K., Jeon J.H. Vascular Calcification – New Insights into Its Mechanism. Int. J. Mol. Sci., 2020; 21 (8): 2685. doi: 10.3390/ijms21082685Wang J., Zhou J.J., Robertson G.R., Lee V.W. Vitamin D in Vascular Calcification: A Double-Edged Sword? Nutrients, 2018; 10 (5): 652. doi: 10.3390/nu10050652Wang J., Zhou J.J., Robertson G.R., Lee V.W. Vitamin D in Vascular Calcification: A Double-Edged Sword? Nutrients, 2018; 10 (5): 652. doi: 10.3390/nu10050652Passeri E., Mazzaccaro D., Sansoni V., Perego S., Nano G., Verdelli C., Lombardi G., Corbetta S. Effects of 12-months treatment with zoledronate or teriparatide on intima-media thickness of carotid artery in women with postmenopausal osteoporosis: A pilot study. Int. J. Immunopathol. Pharmacol., 2019; 33: 1–7. doi: 10.1177/2058738418822439Passeri E., Mazzaccaro D., Sansoni V., Perego S., Nano G., Verdelli C., Lombardi G., Corbetta S. Effects of 12-months treatment with zoledronate or teriparatide on intima-media thickness of carotid artery in women with postmenopausal osteoporosis: A pilot study. Int. J. Immunopathol. Pharmacol., 2019; 33: 1–7. doi: 10.1177/2058738418822439Tong X., Chen M., Song R., Zhao H., Bian J., Gu J., Liu Z. Overexpression of c-Fos reverses osteoprotegerin-mediated suppression of osteoclastogenesis by increasing the Beclin1- induced autophagy. J. Cell Mol. Med., 2021; 25 (2): 937–945. doi: 10.1111/jcmm.16152Tong X., Chen M., Song R., Zhao H., Bian J., Gu J., Liu Z. Overexpression of c-Fos reverses osteoprotegerin-mediated suppression of osteoclastogenesis by increasing the Beclin1- induced autophagy. J. Cell Mol. Med., 2021; 25 (2): 937–945. doi: 10.1111/jcmm.16152Rochette L., Meloux A., Rigal E., Zeller M., Cottin Y., Vergely C. The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases. Pharmacol. Ther., 2018; 182: 115–132. doi: 10.1016/j.pharmthera.2017.08.015Rochette L., Meloux A., Rigal E., Zeller M., Cottin Y., Vergely C. The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases. Pharmacol. Ther., 2018; 182: 115–132. doi: 10.1016/j.pharmthera.2017.08.015Rochette L., Meloux A., Rigal E., Zeller M., Cottin Y., Vergely C. The Role of Osteoprotegerin and Its Ligands in Vascular Function. Int. J. Mol. Sci., 2019; 20 (3): 1–19. doi: 10.3390/ijms20030705Rochette L., Meloux A., Rigal E., Zeller M., Cottin Y., Vergely C. The Role of Osteoprotegerin and Its Ligands in Vascular Function. Int. J. Mol. Sci., 2019; 20 (3): 1–19. doi: 10.3390/ijms20030705Chung J., Kim H.L., Pyo Lee J., Lim W.H., Seo J.B., Kim S.H., Zo J.H., Kim M.A. Association of the Serum Osteoprotegerin Level With Target Organ Damage in Patients at High Risk of Coronary Artery Disease. Circ. J., 2020; 85 (1): 69–76. doi: 10.1253/circj.CJ-20-0675Chung J., Kim H.L., Pyo Lee J., Lim W.H., Seo J.B., Kim S.H., Zo J.H., Kim M.A. Association of the Serum Osteoprotegerin Level With Target Organ Damage in Patients at High Risk of Coronary Artery Disease. Circ. J., 2020; 85 (1): 69–76. doi: 10.1253/circj.CJ-20-0675Yee Lok Z.S., Lyle A.N. Osteopontin in Vascular Disease: Friend or Foe? Arterioscler. Thromb. Vasc. Biol., 2019; 39 (4): 613–622. doi: 10.1161/ATVBAHA.118.311577Yee Lok Z.S., Lyle A.N. Osteopontin in Vascular Disease: Friend or Foe? Arterioscler. Thromb. Vasc. Biol., 2019; 39 (4): 613–622. doi: 10.1161/ATVBAHA.118.311577Scatena M., Liaw L., Giachelli C.M. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler. Thromb. Vasc. Biol., 2007; 27 (11): 2302–2309. doi: 10.1161/ATVBAHA.107.144824Scatena M., Liaw L., Giachelli C.M. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler. Thromb. Vasc. Biol., 2007; 27 (11): 2302–2309. doi: 10.1161/ATVBAHA.107.144824Bäck M., Aranyi T., Cancela M.L., Carracedo M., Conceição 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; doi: 10.3389/fcvm.2018.00196Bäck M., Aranyi T., Cancela M.L., Carracedo M., Conceição 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; doi: 10.3389/fcvm.2018.00196Zwakenberg S.R., de Jong P.A., Hendriks E.J., Westerink J., Spiering W., de Borst G.J., Cramer M.J., Bartstra J.W., Doesburg T., Rutters F., van der Heijden A.A., Schalkwijk C., Schurgers L.J., van der Schouw Y.T., Beulens J.W.J. Intimal and medial calcification in relation to cardiovascular risk factors. PLoS One, 2020; 15 (7): 1–14. doi: 10.1371/journal.pone.0235228Zwakenberg S.R., de Jong P.A., Hendriks E.J., Westerink J., Spiering W., de Borst G.J., Cramer M.J., Bartstra J.W., Doesburg T., Rutters F., van der Heijden A.A., Schalkwijk C., Schurgers L.J., van der Schouw Y.T., Beulens J.W.J. Intimal and medial calcification in relation to cardiovascular risk factors. PLoS One, 2020; 15 (7): 1–14. doi: 10.1371/journal.pone.0235228Lee C.J., Wang J.H., Chen M.L., Yang C.F., Chen Y.C., Hsu B.G. Serum osteoprotegerin is associated with arterial stiffness assessed according to the cardio-ankle vascular index in hypertensive patients. J. Atheroscler. Thromb., 2015; 22 (3): 304–12. doi: 10.5551/jat.25882Lee C.J., Wang J.H., Chen M.L., Yang C.F., Chen Y.C., Hsu B.G. Serum osteoprotegerin is associated with arterial stiffness assessed according to the cardio-ankle vascular index in hypertensive patients. J. Atheroscler. Thromb., 2015; 22 (3): 304–12. doi: 10.5551/jat.25882Maniatis K., Siasos G., Oikonomou E., Vavuranakis M., Zaromytidou M., Mourouzis K., Paraskevopoulos T., Charalambous G., Papavassiliou A.G., Tousoulis D. Osteoprotegerin and Osteopontin Serum Levels are Associated with Vascular Function and Inflammation in Coronary Artery Disease Patients. Curr. Vasc. Pharmacol., 2020; 18 (5): 523–530. doi: 10.2174/1570161117666191022095246Maniatis K., Siasos G., Oikonomou E., Vavuranakis M., Zaromytidou M., Mourouzis K., Paraskevopoulos T., Charalambous G., Papavassiliou A.G., Tousoulis D. Osteoprotegerin and Osteopontin Serum Levels are Associated with Vascular Function and Inflammation in Coronary Artery Disease Patients. Curr. Vasc. Pharmacol., 2020; 18 (5): 523–530. doi: 10.2174/1570161117666191022095246Tousoulis D., Siasos G., Maniatis K., Oikonomou E., Kioufis S., Zaromitidou M., Paraskevopoulos T., Michalea S., Kollia C., Miliou A., Kokkou E., Papavassiliou A.G., Stefanadis C. Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int. J. Cardiol., 2013; 167 (5): 1924–1928. doi: 10.1016/j.ijcard.2012.05.001Tousoulis D., Siasos G., Maniatis K., Oikonomou E., Kioufis S., Zaromitidou M., Paraskevopoulos T., Michalea S., Kollia C., Miliou A., Kokkou E., Papavassiliou A.G., Stefanadis C. Serum osteoprotegerin and osteopontin levels are associated with arterial stiffness and the presence and severity of coronary artery disease. Int. J. Cardiol., 2013; 167 (5): 1924–1928. doi: 10.1016/j.ijcard.2012.05.001Albu A., Fodor D., Bondor C., Crăciun A.M. Bone metabolism regulators and arterial stiffness in postmenopausal women. Maturitas, 2013; 76 (2): 146–150. doi: 10.1016/j.maturitas.2013.07.001Albu A., Fodor D., Bondor C., Crăciun A.M. Bone metabolism regulators and arterial stiffness in postmenopausal women. Maturitas, 2013; 76 (2): 146–150. doi: 10.1016/j.maturitas.2013.07.001Morisawa T., Nakagomi A., Kohashi K., Kosugi M., Kusama Y., Atarashi H., Shimizu W. Osteoprotegerin is Associated With Endothelial Function and Predicts Early Carotid Atherosclerosis in Patients With Coronary Artery Disease. Int. Heart. J., 2015; 56 (6): 605–612. doi: 10.1536/ihj.15-150Morisawa T., Nakagomi A., Kohashi K., Kosugi M., Kusama Y., Atarashi H., Shimizu W. Osteoprotegerin is Associated With Endothelial Function and Predicts Early Carotid Atherosclerosis in Patients With Coronary Artery Disease. Int. Heart. J., 2015; 56 (6): 605–612. doi: 10.1536/ihj.15-150Strobescu-ciobanu C., Giuşcă S.E., Căruntu I.D., Amălinei C., Rusu A., Cojocaru E., Popa R.F., Lupaşcu C.D. Osteopontin and osteoprotegerin in atherosclerotic plaque– are they significant markers of plaque vulnerability? Rom. J. Morphol. Embryol., 2020; 61 (3): 793–801. doi: 10.47162/RJME.61.3.yStrobescu-ciobanu C., Giuşcă S.E., Căruntu I.D., Amălinei C., Rusu A., Cojocaru E., Popa R.F., Lupaşcu C.D. Osteopontin and osteoprotegerin in atherosclerotic plaque– are they significant markers of plaque vulnerability? Rom. J. Morphol. Embryol., 2020; 61 (3): 793–801. doi: 10.47162/RJME.61.3.yCao Y., Cui C., Zhao H., Pan X., Li W., Wang K., Ma A. Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke. Hindawi Disease Markers, 2019; 2019 (090364): 1–7. doi: 10.1155/2019/3090364Cao Y., Cui C., Zhao H., Pan X., Li W., Wang K., Ma A. Plasma Osteoprotegerin Correlates with Stroke Severity and the Occurrence of Microembolic Signals in Patients with Acute Ischemic Stroke. Hindawi Disease Markers, 2019; 2019 (090364): 1–7. doi: 10.1155/2019/3090364Wajda J., Świat M., Owczarek A.J., Holecki M., Duława J., Brzozowska A., Olszanecka-Glinianowicz M., Chudek J. Osteoprotegerin Assessment Improves Prediction of Mortality in Stroke Patients. J. Stroke and Cerebrovascular Diseases. 2019; 28 (5): 1160–1167. doi: 10.1016/j.jstrokecerebrovasdis.2019.01.006Wajda J., Świat M., Owczarek A.J., Holecki M., Duława J., Brzozowska A., Olszanecka-Glinianowicz M., Chudek J. Osteoprotegerin Assessment Improves Prediction of Mortality in Stroke Patients. J. Stroke and Cerebrovascular Diseases. 2019; 28 (5): 1160–1167. doi: 10.1016/j.jstrokecerebrovasdis.2019.01.006Hyseni A., Roest M., Braun S.L., Barendrecht A.D., de Groot P.G., Ndrepepa G., Kastrati A. Chronic dysfunction of the endothelium is associated with mortality in acute coronary syndrome patients. Thromb Res., 2013; 131 (3): 198–203. doi: 10.1016/j.thromres.2012.12.001Hyseni A., Roest M., Braun S.L., Barendrecht A.D., de Groot P.G., Ndrepepa G., Kastrati A. Chronic dysfunction of the endothelium is associated with mortality in acute coronary syndrome patients. Thromb Res., 2013; 131 (3): 198–203. doi: 10.1016/j.thromres.2012.12.001Wang H.H., Xiang G.D. Changes of plasma concentration of osteoprotegerin and its association with endothelial dysfunction before and after hypouricemic therapy in patients with hyperuricemia. Mod. Rheumatol., 2015; 25 (1): 123–127. doi: 10.3109/14397595.2014.926852Wang H.H., Xiang G.D. Changes of plasma concentration of osteoprotegerin and its association with endothelial dysfunction before and after hypouricemic therapy in patients with hyperuricemia. Mod. Rheumatol., 2015; 25 (1): 123–127. doi: 10.3109/14397595.2014.926852Dessein P.H., Lуpez-Mejias R., González-Juanatey C., Genre F., Miranda-Filloy J.A., Llorca J., GonzálezGay M.A. Independent relationship of osteoprotegerin concentrations with endothelial activation and carotid atherosclerosis in patients with severe rheumatoid arthritis. J. Rheumatol., 2014; 41 (3): 429–436. doi: 10.3899/jrheum.131037Dessein P.H., Lуpez-Mejias R., González-Juanatey C., Genre F., Miranda-Filloy J.A., Llorca J., GonzálezGay M.A. Independent relationship of osteoprotegerin concentrations with endothelial activation and carotid atherosclerosis in patients with severe rheumatoid arthritis. J. Rheumatol., 2014; 41 (3): 429–436. doi:Golledge J., Leicht A.S., Crowther R.G., Glanville S., Clancy P., Sangla K.S., Spinks W.L., Quigley F. Determinants of endothelial function in a cohort of patients with peripheral artery disease. Cardiology, 2008; 111 (1): 51–56. doi: 10.1159/0001134283899/jrheum.131037Ge Q., Ruan C.C., Ma Y., Tang X.F., Wu Q.H., Wang J.G., Zhu D.L., Gao P.J. Osteopontin regulates macrophage activation and osteoclast formation in hypertensive patients with vascular calcification. Sci. Rep., 2017; 7 (40253): 1–9. doi: 10.1038/srep40253Golledge J., Leicht A.S., Crowther R.G., Glanville S., Clancy P., Sangla K.S., Spinks W.L., Quigley F. Determinants of endothelial function in a cohort of patients with peripheral artery disease. Cardiology, 2008; 111 (1): 51–56. doi: 10.1159/000113428Schreier M., Schwartze J.T., Landgraf K., Scheuermann K., Erbs S., Herberth G., Pospisilik J.A., Kratzsch J., Kiess W., Körner A. Osteopontin is BMIindependently Related to Early Endothelial Dysfunction in Children. J. Clin. Endocrinol. Metab., 2016; 101 (11): 4161–4169. doi: 10.1210/jc.2016-2238Ge Q., Ruan C.C., Ma Y., Tang X.F., Wu Q.H., Wang J.G., Zhu D.L., Gao P.J. Osteopontin regulates macrophage activation and osteoclast formation in hypertensive patients with vascular calcification. Sci. Rep., 2017; 7 (40253): 1–9. doi: 10.1038/srep40253Secchiero P., Corallini F., Pandolfi A., Consoli A., Candido R., Fabris B., Celeghini C., Capitani S., Zauli G. An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. Am. J. Pathol., 2006; 169 (6): 2236–2244. doi: 10.2353/ajpath.2006.060398Schreier M., Schwartze J.T., Landgraf K., Scheuermann K., Erbs S., Herberth G., Pospisilik J.A., Kratzsch J., Kiess W., Körner A. Osteopontin is BMIindependently Related to Early Endothelial Dysfunction in Children. J. Clin. Endocrinol. Metab., 2016; 101 (11): 4161–4169. doi: 10.1210/jc.2016-2238Rajendran N.D. A study of osteoprotegerin as a predictor of myocardial infarction in type 2 diabetes mellitus patients. The Tamilnadu Dr.M.G.R. Medical University Chennai, 2019.Secchiero P., Corallini F., Pandolfi A., Consoli A., Candido R., Fabris B., Celeghini C., Capitani S., Zauli G. An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. Am. J. Pathol., 2006; 169 (6): 2236–2244. doi: 10.2353/ajpath.2006.060398Kremzer A.A. Plasma osteoprotegerin as a marker of documented coronary atherosclerosis in type two diabetes mellitus patients. Biological Markers in Fundamental and Clinical Medicine, 2019; 3 (1): 100–101. doi: 10.29256/v.03.01.2019.escbm01-89Rajendran N.D. A study of osteoprotegerin as a predictor of myocardial infarction in type 2 diabetes mellitus patients. The Tamilnadu Dr.M.G.R. Medical University Chennai, 2019.Firdouse M.S., Nanda N., Satheesh S., Jasmine M.R. Association of osteoprotegerin and lipid risk factors with severity of stenosis in coronary artery disease patients with diabetes mellitus. Biomedicine. 2020; 40 (1): 32–35. doi: 10.51248/.v40i1.96Kremzer A.A. Plasma osteoprotegerin as a marker of documented coronary atherosclerosis in type two diabetes mellitus patients. Biological Markers in Fundamental and Clinical Medicine, 2019; 3 (1): 100–101. doi: 10.29256/v.03.01.2019.escbm01-89Maddaloni E., Park K., di Guida M., Coraggio L., Luordi C., D’onofrio L., Baroni M.G., Cavallo M.G., D’angelo P., de Cosmo S., Leonetti F., Morano S., Morviducci L., Pozzilli P., Prudente S., Pugliese G., Trischitta V., Holman R.R., King G.L., Buzzetti R. Osteoprotegerin Induces Endothelial Dysfunction and Is Associated with Vascular Complications In Type 2 Diabetes. Diabetes,. 2020; 69 (1): 570–583. doi: 10.2337/db20-570-PFirdouse M.S., Nanda N., Satheesh S., Jasmine M.R. Association of osteoprotegerin and lipid risk factors with severity of stenosis in coronary artery disease patients with diabetes mellitus. Biomedicine. 2020; 40 (1): 32–35. doi: 10.51248/.v40i1.96Schinzari F., Tesauro M., Bertoli A., Valentini A., Veneziani A., Campia U., Cardillo C. Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents. Am. J. Physiol. Endocrinol. Metab., 2019; 317: 658–666. doi: 10.1152/ajpendo.00204.2019Maddaloni E., Park K., di Guida M., Coraggio L., Luordi C., D’onofrio L., Baroni M.G., Cavallo M.G., D’angelo P., de Cosmo S., Leonetti F., Morano S., Morviducci L., Pozzilli P., Prudente S., Pugliese G., Trischitta V., Holman R.R., King G.L., Buzzetti R. Osteoprotegerin Induces Endothelial Dysfunction and Is Associated with Vascular Complications In Type 2 Diabetes. Diabetes,. 2020; 69 (1): 570–583. doi: 10.2337/db20-570-PTorres P.A. Origin of the mediacalcosis in kidney failure. J. Mal. Vasc., 2009; 34 (3): 204–210. doi: 10.1016/j.jmv.2009.02.002Schinzari F., Tesauro M., Bertoli A., Valentini A., Veneziani A., Campia U., Cardillo C. Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents. Am. J. Physiol. Endocrinol. Metab., 2019; 317: 658–666. doi: 10.1152/ajpendo.00204.2019Huang Q.X., Li J.B., Huang N., Huang X., Li Y., Huang F. Elevated Osteoprotegerin Concentration Predicts Increased Risk of Cardiovascular Mortality in Patients with Chronic Kidney Disease: A Systematic Review and MetaAnalysis. Kidney Blood Press Res., 2020; 45: 565–575. doi: 10.1159/000508978Torres P.A. Origin of the mediacalcosis in kidney failure. J. Mal. Vasc., 2009; 34 (3): 204–210. doi: 10.1016/j.jmv.2009.02.002Dıaz M.A., Prado M.D.C., Mora C., Romero R., Cordova R., Qureshi A.R., Paniagua R. Osteoprotegerin is better predictor for cardiovascular and allcause mortality than vascular calcification in patients on peritoneal dialysis. Nephrology Dialysis Transplantation, 2019; 34 (1): 618–626. doi: 10.1093/ndt/gfz106.FP618Huang Q.X., Li J.B., Huang N., Huang X., Li Y., Huang F. Elevated Osteoprotegerin Concentration Predicts Increased Risk of Cardiovascular Mortality in Patients with Chronic Kidney Disease: A Systematic Review and MetaAnalysis. Kidney Blood Press Res., 2020; 45: 565–575. doi: 10.1159/000508978Bozic M., Méndez-Barbero N., Gutiérrez-Muсoz C., Betriu A., Egido J., Fernández E., Martín-Ventura J.L., Valdivielso J.M., Blanco-Colio L.M. Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease. Atherosclerosis, 2018; 270: 13–20. doi: 10.1016/j.atherosclerosis.2018.01.011Dıaz M.A., Prado M.D.C., Mora C., Romero R., Cordova R., Qureshi A.R., Paniagua R. Osteoprotegerin is better predictor for cardiovascular and allcause mortality than vascular calcification in patients on peritoneal dialysis. Nephrology Dialysis Transplantation, 2019; 34 (1): 618–626. doi: 10.1093/ndt/gfz106.FP618Salam S., Gallagher O., Gossiel F., Paggiosi M., Eastell R., Khwaja A. Vascular calcification relationship to vascular biomarkers and bone metabolism in advanced chronic kidney disease. Bone, 2021; 143: 115699. doi: 10.1016/j.bone.2020.115699Bozic M., Méndez-Barbero N., Gutiérrez-Muсoz C., Betriu A., Egido J., Fernández E., Martín-Ventura J.L., Valdivielso J.M., Blanco-Colio L.M. Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease. Atherosclerosis, 2018; 270: 13–20. doi: 10.1016/j.atherosclerosis.2018.01.011Batko K., Krzanowski M., Gajda M., Dumnicka P., Fedak D., Woziwodzka K., Sułowicz W., Kuźniewski M., Litwin J.A., Krzanowska K. Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease. Cytokine, 2019; 121: 154729. doi: 10.1016/j.cyto.2019.05.016Salam S., Gallagher O., Gossiel F., Paggiosi M., Eastell R., Khwaja A. Vascular calcification relationship to vascular biomarkers and bone metabolism in advanced chronic kidney disease. Bone, 2021; 143: 115699. doi: 10.1016/j.bone.2020.115699Fitzpatrick J., Kim E.D., Sozio S.M., Jaar B.G., Estrella M.M., Monroy-Trujillo J.M., Parekh R.S. Calcification Biomarkers, Subclinical Vascular Disease, and Mortality Among Multiethnic Dialysis Patients. Kidney Int. Rep., 2020; 5 (10): 1729–1737. doi: 10.1016/j.ekir.2020.07.033Batko K., Krzanowski M., Gajda M., Dumnicka P., Fedak D., Woziwodzka K., Sułowicz W., Kuźniewski M., Litwin J.A., Krzanowska K. Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease. Cytokine, 2019; 121: 154729. doi: 10.1016/j.cyto.2019.05.016Thanakun S., Na Mahasarakham C.P., Pornprasertsuk- Damrongsri S., Izumi Y. Correlation of plasma osteopontin and osteocalcin with lower renal function in dental patients with carotid artery calcification and tooth loss. J. Oral Biosciences, 2019; 61 (3): 183–189. doi: 10.1016/j.job.2019.06.004Fitzpatrick J., Kim E.D., Sozio S.M., Jaar B.G., Estrella M.M., Monroy-Trujillo J.M., Parekh R.S. Calcification Biomarkers, Subclinical Vascular Disease, and Mortality Among Multiethnic Dialysis Patients. Kidney Int. Rep., 2020; 5 (10): 1729–1737. doi: 10.1016/j.ekir.2020.07.033Keryakos H.K.H., Okaily N.I., Boulis M.A.Y., Salama A.M.S. Osteocalcin and vascular calcification in hemodialysis patients: an observational cohort study. Int. Urol. Nephrol., 2021; 53 (5): 1015–1023. doi: 10.1007/s11255-020-02753-yThanakun S., Na Mahasarakham C.P., Pornprasertsuk- Damrongsri S., Izumi Y. Correlation of plasma osteopontin and osteocalcin with lower renal function in dental patients with carotid artery calcification and tooth loss. J. Oral Biosciences, 2019; 61 (3): 183–189. doi: 10.1016/j.job.2019.06.004Luna-Luna M., Criales-Vera S., Medina-Leyte D., Díaz-Zamudio M., Flores-Zapata A., Cruz-Robles D., Lуpez-Meneses M., Olvera-Cruz S., Ramírez-Marroquín S., Flores-Castillo C., Fragoso J.M., CarreуnTorres E., Vargas-Barrуn J., Vargas-Alarcуn G., Pé-rez-Méndez O. Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques. Diabetes Metab. Syndr. Obes., 2020; 13: 1943–1951. doi: 10.2147/DMSO.S253632Keryakos H.K.H., Okaily N.I., Boulis M.A.Y., Salama A.M.S. Osteocalcin and vascular calcification in hemodialysis patients: an observational cohort study. Int. Urol. Nephrol., 2021; 53 (5): 1015–1023. doi: 10.1007/s11255-020-02753-yLuna-Luna M., Cruz-Robles D., Ávila-Vanzzini N., Herrera- Alarcуn V., Martínez-Reding J., Criales-Vera S., Sandoval-Zárate J., Vargas-Barrуn J., MartínezSánchez C., Tovar-Palacio A.R., Fragoso J.M., Carreуn-Torres E., Vargas-Alarcуn G., Pérez- Méndez O. Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: association with HDL subclasses. Lipids. Health. Dis., 2017; 16 (1): 156. doi: 10.1186/s12944-017-0550-2Luna-Luna M., Criales-Vera S., Medina-Leyte D., Díaz-Zamudio M., Flores-Zapata A., Cruz-Robles D., Lуpez-Meneses M., Olvera-Cruz S., Ramírez-Marroquín S., Flores-Castillo C., Fragoso J.M., CarreуnTorres E., Vargas-Barrуn J., Vargas-Alarcуn G., Pé-rez-Méndez O. Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques. Diabetes Metab. Syndr. Obes., 2020; 13: 1943–1951. doi: 10.2147/DMSO.S253632Luna-Luna M., Cruz-Robles D., Ávila-Vanzzini N., Herrera- Alarcуn V., Martínez-Reding J., Criales-Vera S., Sandoval-Zárate J., Vargas-Barrуn J., MartínezSánchez C., Tovar-Palacio A.R., Fragoso J.M., Carreуn-Torres E., Vargas-Alarcуn G., Pérez- Méndez O. Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: association with HDL subclasses. Lipids. Health. Dis., 2017; 16 (1): 156. doi: 10.1186/s12944-017-0550-2Luna-Luna M., Cruz-Robles D., Ávila-Vanzzini N., Herrera- Alarcуn V., Martínez-Reding J., Criales-Vera S., Sandoval-Zárate J., Vargas-Barrуn J., MartínezSánchez C., Tovar-Palacio A.R., Fragoso J.M., Carreуn-Torres E., Vargas-Alarcуn G., Pérez- Méndez O. Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: association with HDL subclasses. Lipids. Health. Dis., 2017; 16 (1): 156. doi: 10.1186/s12944-017-0550-2

The authors declare that there are no conflicts of interest present.