fcmedicineФундаментальная и клиническая медицинаFundamental and Clinical Medicine2500-07642542-0941КемГМУ10.23946/2500-0764-2020-5-1-78-93fcmedicine-224Research ArticleОБЗОРНЫЕ СТАТЬИREVIEW ARTICLESКальций-фосфатные бионы: на пути к формированию патогенетической концепцииCalcium phosphate bions: towards a pathogenetic concepthttps://orcid.org/0000-0001-8679-4857КутихинА. Г.KutikhinA. G.

Кутихин Антон Геннадьевич - кандидат медицинских наук, заведующий лабораторией фундаментальных аспектов атеросклероза отдела экспериментальной и клинической кардиологии.

650002, Кемерово, Сосновый бульвар, 6

Dr. Anton G. Kutikhin - MD, PhD, Head of the Laboratory for Vascular Biology, Division of Experimental and Clinical Cardiology.

6, Sosnovy Boulevard, Kemerovo, 650002

antonkutikhin@gmail.comФГБНУ Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеванийРоссияResearch Institute for Complex Issues of Cardiovascular DiseasesRussian Federation202028032020517893Copyright © Кутихин А.Г., 20202020Кутихин А.Г.Kutikhin A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://fcm.kemsmu.ru/jour/article/view/224

Перенасыщение крови ионами кальция и фосфора ассоциировано с повышенным риском сердечно-сосудистых событий, однако патофизиологические основы данной клинико-эпидемиологической связи остаются неясными. В ответ на превышение физиологических уровней кальция и фосфора в результате действия минерального шаперона фетуина-А происходит агрегация избыточных минеральных ионов в кальций-фосфатные бионы (КФБ), которые далее необратимо интернали-зуются эндотелиальными клетками, вызывая пермеабилизацию их лизосомальной мембраны и приводя к неспецифическому провоспалительному ответу и клеточной гибели. В сочетании данные процессы приводят к формированию патологического микроокружения, потенцирующего развитие дисфункции эндотелия, остеохондрогенного фенотипического сдвига сосудистых гладкомышечных клеток и воспаления адвентиции; данные последствия, в свою очередь, вызывают формирование неоинтимы и кальцификацию медии. Хотя корреляция между повышенным уровнем КФБ в крови и повышенным риском сердечно-сосудистых событий и сердечно-сосудистой смерти впервые была выявлена у пациентов с хронической болезнью почек, последние исследования указывают на ее присутствие и у пациентов с артериальной гипертензией и ишемической болезнью сердца и без почечной дисфункции, предполагая общий и единый патофизиологический механизм.

В данном обзоре обсуждаются существующие данные о формировании КФБ и их влиянии на развитие различных сердечно-сосудистых заболеваний, методы, которыми они исследуются, и недостатки моделей, применяемых на сегодняшний день для оценки их патофизиологических эффектов и механизмов потенцирования сердечно-сосудистых патологий. Также обсуждается диагностическая значимость измерения уровня КФБ в сыворотке крови и терапевтический потенциал различных видов специфической терапии для когорт пациентов с хронической болезнью почек, ишемической болезнью сердца и ишемией головного мозга.

Supersaturation of blood with calcium and phosphate is associated with higher risk of major adverse cardiovascular events; however, pathophysiological basis of such association remains unclear. Upon an excess of serum calcium and phosphate, mineral chaperone fetuin-A aggregates mineral ions into calcium phosphate bions (CPB, alternatively termed calciprotein particles), which are irreversibly internalised by endothelial cells causing lysosome membrane permeabilisation, non-specific inflammatory response and cell death. Altogether, these processes contribute to pathological microenvironment potentiating endothelial dysfunction, osteochondrogenic differentiation of vascular smooth muscle cells, and adventitial inflammation which in turn culminate into intimal hyperplasia and medial arterial calcification. Albeit the correlation between increased CPB count in the blood and higher risk of cardiovascular events/cardiovascular death has initially been found in patients with chronic kidney disease, recent investigations suggest similar scenario in patients with arterial hypertension and coronary artery disease without renal dysfunction testifying to the general pathophysiological mechanism. Here we discuss the existing data on how CPB do form and how they affect the development of cardiovascular disease. We further consider advantages and shortcomings of the relevant experimental models as well as diagnostic significance of measuring CPB in the serum and clinical potential of anti-CPP therapies for the patients with chronic kidney disease, coronary artery disease, and cerebrovascular disease.

кальций-фосфатные бионыминеральный гомеостазхроническая болезнь почексердечно-сосудистые событиядисфункция эндотелиякальцификация сосудоватеросклерозcalcium phosphate bionsmineral homeostasischronic kidney diseasecardiovascular eventsendothelial dysfunctionvascular calcificationatherosclerosisРабота выполнена при поддержке комплексной программы фундаментальных научных исследований СО РАН в рамках фундаментальной темы НИИ КПССЗ № 0546-2019-0002 «Патогенетическое обоснование разработки имплантатов для сердечно-сосудистой хирургии на основе биосовместимых материалов, с реализацией пациент-ориентированного подхода с использованием математического моделирования, тканевой инженерии и геномных предикторов»This study was supported by the Complex Program of Basic Research under the Siberian Branch of the Russian Academy of Sciences within the Basic Research Topic of Research Institute for Complex Issues of Cardiovascular Diseases № 05462019-0002 “Pathogenetic basis for the development of cardiovascular implants from biocompatible materials using patient-oriented approach, mathematical modeling, tissue engineering, and genomic predictors”ReferencesLind 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):967-973. https://doi.org/10.1016/S0895-4356(97)00104-2.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):967-973. https://doi.org/10.1016/S0895-4356(97)00104-2.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):556-563. https://doi.org/10.1016/j.ahj.2008.05.016.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):556-563. https://doi.org/10.1016/j.ahj.2008.05.016.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):333-339. https://doi.org/10.1161/ATVBAHA.109.196675.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):333-339. https://doi.org/10.1161/ATVBAHA.109.196675.Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321(7255):199-204. https://doi.org/10.1136/bmj.321.7255.199.Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321(7255):199-204. https://doi.org/10.1136/bmj.321.7255.199.Sun ZL, Xie QY, Guo GL, Ma K, Huang YY. Serum fetuin-A levels in patients with cardiovascular disease: a metaanalysis. Biomed Res Int. 2014;2014:691540. https://doi.org/10.1155/2014/691540.Sun ZL, Xie QY, Guo GL, Ma K, Huang YY. Serum fetuin-A levels in patients with cardiovascular disease: a metaanalysis. Biomed Res Int. 2014;2014:691540. https://doi.org/10.1155/2014/691540.El-Abbadi MM, Pai AS, Leaf EM, Yang HY, Bartley BA, Quan KK, Ingalls CM, Liao HW, Giachelli CM. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int. 2009;75(12):1297-1307. https://doi.org/10.1038/ki.2009.83.El-Abbadi MM, Pai AS, Leaf EM, Yang HY, Bartley BA, Quan KK, Ingalls CM, Liao HW, Giachelli CM. Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. Kidney Int. 2009;75(12):1297-1307. https://doi.org/10.1038/ki.2009.83.Sonou T, Ohya M, Yashiro M, Masumoto A, Nakashima Y, Ito T, Mima T, Negi S, Kimura-Suda H, Shigematsu T. Mineral Composition of Phosphate-Induced Calcification in a Rat Aortic Tissue Culture Model. J Atheroscler Thromb. 2015;22(11):1197-1206. https://doi.org/10.5551/jat.28647.Sonou T, Ohya M, Yashiro M, Masumoto A, Nakashima Y, Ito T, Mima T, Negi S, Kimura-Suda H, Shigematsu T. Mineral Composition of Phosphate-Induced Calcification in a Rat Aortic Tissue Culture Model. J Atheroscler Thromb. 2015;22(11):1197-1206. https://doi.org/10.5551/jat.28647.Yurdagul A Jr, Finney AC, Woolard MD, Orr AW. The arterial microenvironment: the where and why of atherosclerosis. Biochem J. 2016; 473 (10): 1281-1295. https://doi.org/10.1042/BJ20150844.Yurdagul A Jr, Finney AC, Woolard MD, Orr AW. The arterial microenvironment: the where and why of atherosclerosis. Biochem J. 2016; 473 (10): 1281-1295. https://doi.org/10.1042/BJ20150844.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.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.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):13333-13341. https://doi.org/10.1074/jbc.M210868200.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):13333-13341. https://doi.org/10.1074/jbc.M210868200.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.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.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. Glarich 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.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. Glarich 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.Back M, Aranyi T, Cancela ML, Carracedo M, Conceigao 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.Back M, Aranyi T, Cancela ML, Carracedo M, Conceigao 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.Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm. 2008;78:131-156. https://doi.org/10.1016/S0083-6729(07)00007-6.Berkner KL. Vitamin K-dependent carboxylation. Vitam Horm. 2008;78:131-156. https://doi.org/10.1016/S0083-6729(07)00007-6.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):217-226. https://doi.org/10.1016/j.molmed.2012.12.008.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):217-226. https://doi.org/10.1016/j.molmed.2012.12.008.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 Y-carboxylation status. Mol Nutr Food Res. 2014;58(8):1636-1646. https://doi.org/10.1002/mnfr.201300941.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 Y-carboxylation status. Mol Nutr Food Res. 2014;58(8):1636-1646. https://doi.org/10.1002/mnfr.201300941.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.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.Mencke R, Hillebrands JL; NIGRAM consortium. The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology. Ageing Res Rev. 2017;35:124-146. https://doi.org/10.1016/j.arr.2016.09.001.Mencke R, Hillebrands JL; NIGRAM consortium. The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology. Ageing Res Rev. 2017;35:124-146. https://doi.org/10.1016/j.arr.2016.09.001.Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin Circ Res. 2004;95(11):1046-1057.Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin Circ Res. 2004;95(11):1046-1057.Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12(9):1260-1268.Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12(9):1260-1268.Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000;192(4):463-474.Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med. 2000;192(4):463-474.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):2035-2046.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):2035-2046.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.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.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):14815-14825. https://doi.org/10.1074/jbc.M709938200.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):14815-14825. https://doi.org/10.1074/jbc.M709938200.Heiss A, Jahnen-Dechent W, Endo H, Schwahn D. Structural dynamics of a colloidal protein-mineral complex bestowing on calcium phosphate a high solubility in biological fluids. Biointerphases. 2007;2(1):16-20. https://doi.org/10.1116/1.2714924.Heiss A, Jahnen-Dechent W, Endo H, Schwahn D. Structural dynamics of a colloidal protein-mineral complex bestowing on calcium phosphate a high solubility in biological fluids. Biointerphases. 2007;2(1):16-20. https://doi.org/10.1116/1.2714924.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):3986-3995. https://doi.org/10.1016/j.bpj.2010.10.030.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):3986-3995. https://doi.org/10.1016/j.bpj.2010.10.030.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 time-resolved small-angle X-ray study. Chembiochem. 2009;10(4):735-740. https://doi.org/10.1002/cbic.200800719.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 time-resolved small-angle X-ray study. Chembiochem. 2009;10(4):735-740. https://doi.org/10.1002/cbic.200800719.Chang JC, Miura RM. Regulatory inhibition of biological tissue mineralization by calcium phosphate through post-nucleation shielding by fetuin-A. J Chem Phys. 2016;144(15):154906. https://doi.org/10.1063/1.4946002.Chang JC, Miura RM. Regulatory inhibition of biological tissue mineralization by calcium phosphate through post-nucleation shielding by fetuin-A. J Chem Phys. 2016;144(15):154906. https://doi.org/10.1063/1.4946002.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.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.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. Apoptosis-mediated 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.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. Apoptosis-mediated 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.Molenaar FM, van Reekum FE, Rookmaaker MB, Abrahams AC, van Jaarsveld BC. Extraosseous calcification in end-stage renal disease: from visceral organs to vasculature. Semin Dial. 2014; 27 (5): 477-487. https://doi.org/10.1111/sdi.12177.Molenaar FM, van Reekum FE, Rookmaaker MB, Abrahams AC, van Jaarsveld BC. Extraosseous calcification in end-stage renal disease: from visceral organs to vasculature. Semin Dial. 2014; 27 (5): 477-487. https://doi.org/10.1111/sdi.12177.Nigwekar SU, Kroshinsky D, Nazarian RM, Goverman J, Malhotra R, Jackson VA, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015; 66 (1): 133146. https://doi.org/10.1053/j.ajkd.2015.01.034.Nigwekar SU, Kroshinsky D, Nazarian RM, Goverman J, Malhotra R, Jackson VA, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015; 66 (1): 133146. https://doi.org/10.1053/j.ajkd.2015.01.034.GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1151-1210. https://doi.org/10.1016/S0140-6736(17)32152-9.GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1151-1210. https://doi.org/10.1016/S0140-6736(17)32152-9.Jensen HA, Mehta JL. Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis. Expert Rev Cardiovasc Ther. 2016; 14 (9): 1021-1033. https://doi.org/10.1080/14779072.2016.1207527.Jensen HA, Mehta JL. Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis. Expert Rev Cardiovasc Ther. 2016; 14 (9): 1021-1033. https://doi.org/10.1080/14779072.2016.1207527.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.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.Mulligan-Kehoe MJ, Simons M. Vasa Vasorum in Normal and Diseased Arteries. Circulation. 2014;129:2557-2566. https://doi.org/10.1161/CIRCULATIONAHA.113.007189.Mulligan-Kehoe MJ, Simons M. Vasa Vasorum in Normal and Diseased Arteries. Circulation. 2014;129:2557-2566. https://doi.org/10.1161/CIRCULATIONAHA.113.007189.Michel JB, Thaunat O, Houard X, Meilhac O, Caligiuri G, Nicoletti A. Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol. 2007;27:1259-1268. https://doi.org/10.1161/ATVBAHA.106.137851;Michel JB, Thaunat O, Houard X, Meilhac O, Caligiuri G, Nicoletti A. Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol. 2007;27:1259-1268. https://doi.org/10.1161/ATVBAHA.106.137851;Gossl M, Malyar NM, Rosol M, Beighley PE, Ritman EL. Impact of coronary vasa vasorum functional structure on coronary vessel wall perfusion distribution. Am J Physiol Heart Circ Physiol. 2003;285:H2019-H2026. https://doi.org/10.1152/ajpheart.00399.2003;Gossl M, Malyar NM, Rosol M, Beighley PE, Ritman EL. Impact of coronary vasa vasorum functional structure on coronary vessel wall perfusion distribution. Am J Physiol Heart Circ Physiol. 2003;285:H2019-H2026. https://doi.org/10.1152/ajpheart.00399.2003;Shi Y, O’Brien JE, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation. 1996;94:1655-1664. https://doi.org/10.1161/01.CIR.94.7.1655;Shi Y, O’Brien JE, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation. 1996;94:1655-1664. https://doi.org/10.1161/01.CIR.94.7.1655;Shi Y. Pieniek M, Fard A, O’Brien J, Mannion JD, Zalewski A. Adventitial remodeling after coronary arterial injury. Circulation. 1996;93:340-348. https://doi.org/10.1161/01.CIR.93.2.340;Shi Y. Pieniek M, Fard A, O’Brien J, Mannion JD, Zalewski A. Adventitial remodeling after coronary arterial injury. Circulation. 1996;93:340-348. https://doi.org/10.1161/01.CIR.93.2.340;Jabs A, Okamoto E, Vinten-Johansen J, Bauriedel G, Wilcox JN. Sequential patterns of chemokine- and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries. Atherosclerosis. 2007;192:75-84. https://doi.org/10.1016/j.atherosclerosis.2006.05.050;Jabs A, Okamoto E, Vinten-Johansen J, Bauriedel G, Wilcox JN. Sequential patterns of chemokine- and chemokine receptor-synthesis following vessel wall injury in porcine coronary arteries. Atherosclerosis. 2007;192:75-84. https://doi.org/10.1016/j.atherosclerosis.2006.05.050;Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R, Funk CD, Kaiser B, Habenicht AJ. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:2386-2391. https://doi.org/10.1161/01.ATV.0000187470.31662.fe;Moos MP, John N, Grabner R, Nossmann S, Gunther B, Vollandt R, Funk CD, Kaiser B, Habenicht AJ. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:2386-2391. https://doi.org/10.1161/01.ATV.0000187470.31662.fe;Herrmann J, Lerman LO, Rodriguez-Porcel M, Holmes DR, Richardson DM, Ritman EL, Lerman A. Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res. 2001;51:762-766. https://doi.org/10.1016/S0008-6363(01)00347-9;Herrmann J, Lerman LO, Rodriguez-Porcel M, Holmes DR, Richardson DM, Ritman EL, Lerman A. Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res. 2001;51:762-766. https://doi.org/10.1016/S0008-6363(01)00347-9;Bertazzo S, Gentleman E, Cloyd KL, Chester AH, Yacoub MH, Stevens MM. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat Mater. 2013;12(6): 576-583. https://doi.org/10.1038/nmat3627.Bertazzo S, Gentleman E, Cloyd KL, Chester AH, Yacoub MH, Stevens MM. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat Mater. 2013;12(6): 576-583. https://doi.org/10.1038/nmat3627.Schlieper G, Grotemeyer D, Aretz A, Schurgers LJ, Kruger T, Rehbein H, Weirich TE, Westenfeld R, Brandenburg VM, Eitner F, Mayer J, Floege J, Sandmann W, Ketteler M. Analysis of calcifications in patients with coral reef aorta. Ann Vasc Surg. 2010;24(3): 408-414. https://doi.org/10.1016/j.avsg.2009.11.006.Schlieper G, Grotemeyer D, Aretz A, Schurgers LJ, Kruger T, Rehbein H, Weirich TE, Westenfeld R, Brandenburg VM, Eitner F, Mayer J, Floege J, Sandmann W, Ketteler M. Analysis of calcifications in patients with coral reef aorta. Ann Vasc Surg. 2010;24(3): 408-414. https://doi.org/10.1016/j.avsg.2009.11.006.Schlieper G, Aretz A, Verberckmoes SC, Kruger T, Behets GJ, Ghadimi R, Weirich TE, Rohrmann D, Langer S, Tordoir JH, Amann K, Westenfeld R, Brandenburg VM, D'Haese PC, Mayer J, Ketteler M, McKee MD, Floege J. Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol. 2010;21(4): 689-696. https://doi.org/10.1681/ASN.2009080829.Schlieper G, Aretz A, Verberckmoes SC, Kruger T, Behets GJ, Ghadimi R, Weirich TE, Rohrmann D, Langer S, Tordoir JH, Amann K, Westenfeld R, Brandenburg VM, D'Haese PC, Mayer J, Ketteler M, McKee MD, Floege J. Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol. 2010;21(4): 689-696. https://doi.org/10.1681/ASN.2009080829.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.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.Smith ER, Ford ML, Tomlinson LA, Bodenham E, McMahon LP, Farese S, Rajkumar C, Holt SG, Pasch A. Serum calcification propensity predicts all-cause mortality in predialysis CKD. J Am Soc Nephrol. 2014;25(2):339-348. https://doi.org/10.1681/ASN.2013060635.Smith ER, Ford ML, Tomlinson LA, Bodenham E, McMahon LP, Farese S, Rajkumar C, Holt SG, Pasch A. Serum calcification propensity predicts all-cause mortality in predialysis CKD. J Am Soc Nephrol. 2014;25(2):339-348. https://doi.org/10.1681/ASN.2013060635.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.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.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):239-248. https://doi.org/10.1681/ASN.2014070670.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):239-248. https://doi.org/10.1681/ASN.2014070670.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):204-212. https://doi.org/10.1111/ajt.13443.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):204-212. https://doi.org/10.1111/ajt.13443.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.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.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.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.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 May 15. pii: S0914-5087(19)30115-30117. https://doi.org/10.1016/j.jjcc.2019.04.008.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 May 15. pii: S0914-5087(19)30115-30117. https://doi.org/10.1016/j.jjcc.2019.04.008.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.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.Miura Y, Iwazu Y, Shiizaki K, Akimoto T, Kotani K, Kurabayashi M, Kurosu H, Kuro-O M. Identification and quantification of plasma calciprotein particles with distinct physical properties in patients with chronic kidney disease. Sci Rep. 2018;8(1):1256. https://doi.org/10.1038/s41598-018-19677-4.Miura Y, Iwazu Y, Shiizaki K, Akimoto T, Kotani K, Kurabayashi M, Kurosu H, Kuro-O M. Identification and quantification of plasma calciprotein particles with distinct physical properties in patients with chronic kidney disease. Sci Rep. 2018;8(1):1256. https://doi.org/10.1038/s41598-018-19677-4.Chen W, Anokhina V, Dieudonne G, Abramowitz MK, Kashyap R, Yan C, Wu TT, de Mesy Bentley KL, Miller BL, Bushinsky DA. Patients with advanced chronic kidney disease and vascular calcification have a large hydrodynamic radius of secondary calciprotein particles. Nephrol Dial Transplant. 2019;34(6):992-1000. https://doi.org/10.1093/ndt/gfy117.Chen W, Anokhina V, Dieudonne G, Abramowitz MK, Kashyap R, Yan C, Wu TT, de Mesy Bentley KL, Miller BL, Bushinsky DA. Patients with advanced chronic kidney disease and vascular calcification have a large hydrodynamic radius of secondary calciprotein particles. Nephrol Dial Transplant. 2019;34(6):992-1000. https://doi.org/10.1093/ndt/gfy117.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.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.Smith ER, Hanssen E, McMahon LP, Holt SG. Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage. PLoS One. 2013;8(4):e60904. https://doi.org/10.1371/journal.pone.0060904.Smith ER, Hanssen E, McMahon LP, Holt SG. Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage. PLoS One. 2013;8(4):e60904. https://doi.org/10.1371/journal.pone.0060904.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 Circulatin g 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.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 Circulatin g 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.Smith ER, Hewitson TD, Hanssen E, Holt SG. Biochemical transformation of calciprotein particles in uraemia. Bone. 2018;110:355-367. https://doi.org/10.1016/j.bone.2018.02.023.Smith ER, Hewitson TD, Hanssen E, Holt SG. Biochemical transformation of calciprotein particles in uraemia. Bone. 2018;110:355-367. https://doi.org/10.1016/j.bone.2018.02.023.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):1241-1250. https://doi.org/10.1001/jama.2013.2107.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):1241-1250. https://doi.org/10.1001/jama.2013.2107.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.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.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 cross-sectional pilot study. Nephrology (Carlton). 2018;23(3):226-230. https://doi.org/10.1111/nep.12994.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 cross-sectional pilot study. Nephrology (Carlton). 2018;23(3):226-230. https://doi.org/10.1111/nep.12994.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.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.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):481-488. https://doi.org/10.1097/HCO.0000000000000096.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):481-488. https://doi.org/10.1097/HCO.0000000000000096.Foreman H, Trujillo TT. The metabolism of C14 labeled ethylenediaminetetraacetic acid in human beings. J Lab Clin Med. 1954;43(4):566-571.Foreman H, Trujillo TT. The metabolism of C14 labeled ethylenediaminetetraacetic acid in human beings. J Lab Clin Med. 1954;43(4):566-571.Young JD, Martel J, Young D, Young A, Hung CM, Young L, Chao YJ, Young J, Wu CY. Characterization of granulations of calcium and apatite in serum as pleomorphic mineralo-protein complexes and as precursors of putative nanobacteria. PLoS One. 2009; 4 (5): e5421. https://doi.org/10.1371/journal.pone.0005421.Young JD, Martel J, Young D, Young A, Hung CM, Young L, Chao YJ, Young J, Wu CY. Characterization of granulations of calcium and apatite in serum as pleomorphic mineralo-protein complexes and as precursors of putative nanobacteria. PLoS One. 2009; 4 (5): e5421. https://doi.org/10.1371/journal.pone.0005421.Peng HH, Wu CY, Young D et al. Physicochemical and biological properties of biomimetic mineralo-protein nanoparticles formed spontaneously in biological fluids. Small. 2013;9(13):2297-2307. https://doi.org/10.1002/smll.201202270.Peng HH, Wu CY, Young D et al. Physicochemical and biological properties of biomimetic mineralo-protein nanoparticles formed spontaneously in biological fluids. Small. 2013;9(13):2297-2307. https://doi.org/10.1002/smll.201202270.Lebre F, Sridharan R, Sawkins MJ et al. The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation. Sci Rep. 2017;7(1):2922. https://doi.org/10.1038/s41598-017-03086-0.Lebre F, Sridharan R, Sawkins MJ et al. The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation. Sci Rep. 2017;7(1):2922. https://doi.org/10.1038/s41598-017-03086-0.Xu Z, Liu C, Wei J, Sun J. Effects of four types of hydroxya patite nanoparticles with different nanocrystal morphologies and sizes on apoptosis in rat osteoblasts. J Appl Toxicol. 2012;32(6):429-435. https://doi.org/10.1002/jat.1745.Xu Z, Liu C, Wei J, Sun J. Effects of four types of hydroxya patite nanoparticles with different nanocrystal morphologies and sizes on apoptosis in rat osteoblasts. J Appl Toxicol. 2012;32(6):429-435. https://doi.org/10.1002/jat.1745.Zhao X, Ng S, Heng BC, Guo J, Ma L, Tan TT, Ng KW, Loo SC. Cytotoxicity of hydroxyapatite nanoparticles is shape and cell dependent. Arch Toxicol. 2013; 87(6):1037-1052. doi: 10.1007/s00204-012-0827-1.Zhao X, Ng S, Heng BC, Guo J, Ma L, Tan TT, Ng KW, Loo SC. Cytotoxicity of hydroxyapatite nanoparticles is shape and cell dependent. Arch Toxicol. 2013; 87(6):1037-1052. doi: 10.1007/s00204-012-0827-1.Zhang B, Sai Lung P, Zhao S et al. Shape dependent cytotoxicity of PLGA-PEG nanoparticles on human cells. Sci Rep. 2017;7(1):7315. https://doi.org/10.1038/s41598-017-07588-9.Zhang B, Sai Lung P, Zhao S et al. Shape dependent cytotoxicity of PLGA-PEG nanoparticles on human cells. Sci Rep. 2017;7(1):7315. https://doi.org/10.1038/s41598-017-07588-9.Shi X, Zhou K, Huang F, Wang C. Interaction of hydroxyapatite nanoparticles with endothelial cells: internalization and inhibition of angiogenesis in vitro through the PI3K/Akt pathway. Int J Nanomedicine. 2017;12:5781-5795. https://doi.org/10.2147/IJN.S140179.Shi X, Zhou K, Huang F, Wang C. Interaction of hydroxyapatite nanoparticles with endothelial cells: internalization and inhibition of angiogenesis in vitro through the PI3K/Akt pathway. Int J Nanomedicine. 2017;12:5781-5795. https://doi.org/10.2147/IJN.S140179.Richards JM, Kunitake JAMR, Hunt HB, Wnorowski AN, Lin DW, Boskey AL, Donnelly E, Estroff LA, Butcher JT. Crystallinity of hydroxyapatite drives myofibroblastic activation and calcification in aortic valves. Acta Biomater. 2018;71:24-36. https://doi.org/10.1016/j.actbio.2018.02.024.Richards JM, Kunitake JAMR, Hunt HB, Wnorowski AN, Lin DW, Boskey AL, Donnelly E, Estroff LA, Butcher JT. Crystallinity of hydroxyapatite drives myofibroblastic activation and calcification in aortic valves. Acta Biomater. 2018;71:24-36. https://doi.org/10.1016/j.actbio.2018.02.024.Santos C, Turiel S, Sousa Gomes P, Costa E, Santos-Silva A, Quadros P, Duarte J, Battistuzzo S, Fernandes MH. Vascular biosafety of commercial hydroxyapatite particles: discrepancy between blood compatibility assays and endothelial cell behavior. J Nanobiotechnology. 2018;16(1):27. https://doi.org/10.1186/s12951-018-0357-y.Santos C, Turiel S, Sousa Gomes P, Costa E, Santos-Silva A, Quadros P, Duarte J, Battistuzzo S, Fernandes MH. Vascular biosafety of commercial hydroxyapatite particles: discrepancy between blood compatibility assays and endothelial cell behavior. J Nanobiotechnology. 2018;16(1):27. https://doi.org/10.1186/s12951-018-0357-y.Love SA, Maurer-Jones MA, Thompson JW, Lin YS, Haynes CL. Assessing nanoparticle toxicity. Annu Rev Anal Chem (Palo Alto Calif). 2012; 5: 181-205. https://doi.org/10.1146/annurev-anchem-062011-143134.Love SA, Maurer-Jones MA, Thompson JW, Lin YS, Haynes CL. Assessing nanoparticle toxicity. Annu Rev Anal Chem (Palo Alto Calif). 2012; 5: 181-205. https://doi.org/10.1146/annurev-anchem-062011-143134.Lai DY. Toward toxicity testing of nanomaterials in the 21st century: a paradigm for moving forward. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012; 4 (1): 1-15. https://doi.org/10.1002/wnan.162.Lai DY. Toward toxicity testing of nanomaterials in the 21st century: a paradigm for moving forward. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012; 4 (1): 1-15. https://doi.org/10.1002/wnan.162.Sukhanova A, Bozrova S, Sokolov P, Berestovoy M, Karaulov A, Nabiev I. Dependence of Nanoparticle Toxicity on Their Physical and Chemical Properties. Nanoscale Res Lett. 2018; 13 (1): 44. https://doi.org/10.1186/s11671-018-2457-x.Sukhanova A, Bozrova S, Sokolov P, Berestovoy M, Karaulov A, Nabiev I. Dependence of Nanoparticle Toxicity on Their Physical and Chemical Properties. Nanoscale Res Lett. 2018; 13 (1): 44. https://doi.org/10.1186/s11671-018-2457-x.Martel J, Young D, Young A, Wu CY, Chen CD, Yu JS, Young JD. Comprehensive proteomic analysis of mineral nanoparticles derived from human body fluids and analyzed by liquid chromatography-tandem mass spectrometry. Anal Biochem. 2011;418(1):111-125. https://doi.org/10.1016/j.ab.2011.06.018.Martel J, Young D, Young A, Wu CY, Chen CD, Yu JS, Young JD. Comprehensive proteomic analysis of mineral nanoparticles derived from human body fluids and analyzed by liquid chromatography-tandem mass spectrometry. Anal Biochem. 2011;418(1):111-125. https://doi.org/10.1016/j.ab.2011.06.018.Martel J, Wu CY, Hung CY, Wong TY, Cheng AJ, Cheng ML, Shiao MS, Young JD. Fatty acids and small organic compounds bind to mineralo-organic nanoparticles derived from human body fluids as revealed by metabolomic analysis. Nanoscale. 2016; 8 (10): 5537-5545. https://doi.org/10.1039/c5nr08116e.Martel J, Wu CY, Hung CY, Wong TY, Cheng AJ, Cheng ML, Shiao MS, Young JD. Fatty acids and small organic compounds bind to mineralo-organic nanoparticles derived from human body fluids as revealed by metabolomic analysis. Nanoscale. 2016; 8 (10): 5537-5545. https://doi.org/10.1039/c5nr08116e.Wu CY, Martel J, Young JD. Comprehensive organic profiling of biological particles derived from blood. Sci Rep. 2018; 8 (1): 11310. https://doi.org/10.1038/s41598-018-29573-6.Wu CY, Martel J, Young JD. Comprehensive organic profiling of biological particles derived from blood. Sci Rep. 2018; 8 (1): 11310. https://doi.org/10.1038/s41598-018-29573-6.Wu CY, Young D, Martel J, Young JD. A story told by a single nanoparticle in the body fluid: demonstration of dissolution-reprecipitation of nanocrystals in a biological system. Nanomedicine (Lond). 2015;10(17):2659-2676. https://doi.org/10.2217/nnm.15.88.Wu CY, Young D, Martel J, Young JD. A story told by a single nanoparticle in the body fluid: demonstration of dissolution-reprecipitation of nanocrystals in a biological system. Nanomedicine (Lond). 2015;10(17):2659-2676. https://doi.org/10.2217/nnm.15.88.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 calc iprotein particles and enhanced by tumor necrosis factor-a. Atherosclerosis. 2016;251:404-414. https://doi.org/10.1016/j.atherosclerosis.2016.05.044.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 calc iprotein particles and enhanced by tumor necrosis factor-a. Atherosclerosis. 2016;251:404-414. https://doi.org/10.1016/j.atherosclerosis.2016.05.044.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 Sep 4;9:1991. https://doi.org/10.3389/fimmu.2018.01991.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 Sep 4;9:1991. https://doi.org/10.3389/fimmu.2018.01991.Price PA, Thomas GR, Pardini AW, Figueira WF, Caputo JM, Williamson MK. Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats. J Biol Chem. 2002;277(6):3926-3934.Price PA, Thomas GR, Pardini AW, Figueira WF, Caputo JM, Williamson MK. Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats. J Biol Chem. 2002;277(6):3926-3934.Price PA, Caputo JM, Williamson MK. Bone origin of the serum complex of calcium, phosphate, fetuin, and matrix Gla protein: biochemical evidence for the cancellous boneremodeling compartment. J Bone Miner Res. 2002;17(7):1171-1179.Price PA, Caputo JM, Williamson MK. Bone origin of the serum complex of calcium, phosphate, fetuin, and matrix Gla protein: biochemical evidence for the cancellous boneremodeling compartment. J Bone Miner Res. 2002;17(7):1171-1179.Price PA, Williamson MK, Nguyen TM, Than TN. Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat. J Biol Chem. 2004;279(3):1594-600.Price PA, Williamson MK, Nguyen TM, Than TN. Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat. J Biol Chem. 2004;279(3):1594-600.Price PA, Nguyen TM, Williamson MK. Biochemical characterization of the serum fetuin-mineral complex. J Biol Chem. 2003;278(24):22153-22160.Price PA, Nguyen TM, Williamson MK. Biochemical characterization of the serum fetuin-mineral complex. J Biol Chem. 2003;278(24):22153-22160.Matsui I, Hamano T, Mikami S, Fujii N, Takabatake Y, Nagasawa Y, Kawada N, Ito T, Rakugi H, Imai E, Isaka Y. Fu lly phosphorylated fetuin-A forms a mineral complex in the serum of rats with adenine-induced renal failure. Kidney Int. 2009;75(9):915-928. https://doi.org/10.1038/ki.2008.700.Matsui I, Hamano T, Mikami S, Fujii N, Takabatake Y, Nagasawa Y, Kawada N, Ito T, Rakugi H, Imai E, Isaka Y. Fu lly phosphorylated fetuin-A forms a mineral complex in the serum of rats with adenine-induced renal failure. Kidney Int. 2009;75(9):915-928. https://doi.org/10.1038/ki.2008.700.Yamada S, Tokumoto M, Tatsumoto N, Tsuruya K, Kitazono T, Ooboshi H. Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats. Life Sci. 2016;146:117-123. https://doi.org/10.1016/j.lfs.2015.12.050.Yamada S, Tokumoto M, Tatsumoto N, Tsuruya K, Kitazono T, Ooboshi H. Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats. Life Sci. 2016;146:117-123. https://doi.org/10.1016/j.lfs.2015.12.050.Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. J Biol Chem. 2003;278(24):22144-22152.Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. J Biol Chem. 2003;278(24):22144-22152.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 fetuin-A--containing calciprotein particles is mediated by scavenger receptor-A. Circ Res. 2012;111(5):575-584. https://doi.org/10.1161/CIRCRESAHA.111.261479.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 fetuin-A--containing calciprotein particles is mediated by scavenger receptor-A. Circ Res. 2012;111(5):575-584. https://doi.org/10.1161/CIRCRESAHA.111.261479.Schwartz MA, Lieske JC, Kumar V, Farell-Baril G, Miller VM. Human-derived nanoparticles and vascular response to injury in rabbit carotid arteries: proof of principle. Int J Nanomedicine. 2008;3(2):243-248.Schwartz MA, Lieske JC, Kumar V, Farell-Baril G, Miller VM. Human-derived nanoparticles and vascular response to injury in rabbit carotid arteries: proof of principle. Int J Nanomedicine. 2008;3(2):243-248.Cenizo Revuelta N, Gonzalez-Fajardo JA, Bratos MA, Alvarez-Gago T, Aguirre B, Vaquero C. Role of calcifying nanoparticle in the development of hyperplasia and vascular calcification in an animal model. Eur J Vasc Endovasc Surg. 2014;47(6):640-646. https://doi.org/10.1016/j.ejvs.2014.03.002.Cenizo Revuelta N, Gonzalez-Fajardo JA, Bratos MA, Alvarez-Gago T, Aguirre B, Vaquero C. Role of calcifying nanoparticle in the development of hyperplasia and vascular calcification in an animal model. Eur J Vasc Endovasc Surg. 2014;47(6):640-646. https://doi.org/10.1016/j.ejvs.2014.03.002.Hunter LW, Charlesworth JE, Yu S, Lieske JC, Miller VM. Calcifying nanoparticles promote mineralization in vascular smooth muscle cells: implications for atherosclerosis. Int J Nanomedicine. 2014;9:2689-2698. https://doi.org/10.2147/IJN.S63189.Hunter LW, Charlesworth JE, Yu S, Lieske JC, Miller VM. Calcifying nanoparticles promote mineralization in vascular smooth muscle cells: implications for atherosclerosis. Int J Nanomedicine. 2014;9:2689-2698. https://doi.org/10.2147/IJN.S63189.Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AVet al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. https://doi.org/10.1038/s41418-017-0012-4.Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AVet al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. https://doi.org/10.1038/s41418-017-0012-4.Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31(5):969-979. https://doi.org/10.1161/ATVBAHA.110.207415.Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31(5):969-979. https://doi.org/10.1161/ATVBAHA.110.207415.Ramji DP, Davies TS. Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev. 2015;26(6):673-685. https://doi.org/10.1016/j.cytogfr.2015.04.003.Ramji DP, Davies TS. Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev. 2015;26(6):673-685. https://doi.org/10.1016/j.cytogfr.2015.04.003.Callegari A, Coons ML, Ricks JL, Rosenfeld ME, Scatena M. Increased calcification in osteoprotegerin-deficient smooth muscle cells: Dependence on receptor activator of NF-kB ligand and interleukin 6. J Vasc Res. 2014;51(2):118-131. https://doi.org/10.1159/000358920.Callegari A, Coons ML, Ricks JL, Rosenfeld ME, Scatena M. Increased calcification in osteoprotegerin-deficient smooth muscle cells: Dependence on receptor activator of NF-kB ligand and interleukin 6. J Vasc Res. 2014;51(2):118-131. https://doi.org/10.1159/000358920.Zickler D, Luecht C, Willy K, Chen L, Witowski J, Girndt M, Fiedler R, Storr M, Kamhieh-Milz J, Schoon J, Geissler S, Ringden O, Schindler R, Moll G, Dragun D, Catar R. Tumour necrosis factor-alpha in uraemic serum promotes osteoblastic transition and calcification of vascular smooth muscle cells via extracellular signal-regulated kinases and activator protein 1/c-FOS-mediated induction of interleukin 6 expression. Nephrol Dial Transplant. 2018;33(4):574-585. https://doi.org/10.1093/ndt/gfx316.Zickler D, Luecht C, Willy K, Chen L, Witowski J, Girndt M, Fiedler R, Storr M, Kamhieh-Milz J, Schoon J, Geissler S, Ringden O, Schindler R, Moll G, Dragun D, Catar R. Tumour necrosis factor-alpha in uraemic serum promotes osteoblastic transition and calcification of vascular smooth muscle cells via extracellular signal-regulated kinases and activator protein 1/c-FOS-mediated induction of interleukin 6 expression. Nephrol Dial Transplant. 2018;33(4):574-585. https://doi.org/10.1093/ndt/gfx316.Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res. 2018;114(4):590-600. https://doi.org/10.1093/cvr/cvy010.Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res. 2018;114(4):590-600. https://doi.org/10.1093/cvr/cvy010.Allahverdian S, Chaabane C, Boukais K, Francis GA, Bochaton-Piallat ML. Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovasc Res. 2018;114(4):540-550. https://doi.org/10.1093/cvr/cvy022.Allahverdian S, Chaabane C, Boukais K, Francis GA, Bochaton-Piallat ML. Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovasc Res. 2018;114(4):540-550. https://doi.org/10.1093/cvr/cvy022.Iyemere VP, Proudfoot D, Weissberg PL, Shanahan CM. Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification. J Intern Med. 2006;260(3):192-210. https://doi.org/10.1111/j.1365-2796.2006.01692.x.Iyemere VP, Proudfoot D, Weissberg PL, Shanahan CM. Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification. J Intern Med. 2006;260(3):192-210. https://doi.org/10.1111/j.1365-2796.2006.01692.x.Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. CircRes. 2011;109(6):697-711. https://doi.org/10.1161/CIRCRESAHA.110.234914.Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. CircRes. 2011;109(6):697-711. https://doi.org/10.1161/CIRCRESAHA.110.234914.Kapustin AN, Davies JD, Reynolds JL, McNair R, Jones GT, Sidibe A, Schurgers LJ, Skepper JN, Proudfoot D, Mayr M, Shanahan CM. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res. 2011;109(1):e1-12. https://doi.org/10.1161/CIRCRESAHA.110.238808.Kapustin AN, Davies JD, Reynolds JL, McNair R, Jones GT, Sidibe A, Schurgers LJ, Skepper JN, Proudfoot D, Mayr M, Shanahan CM. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res. 2011;109(1):e1-12. https://doi.org/10.1161/CIRCRESAHA.110.238808.Kapustin AN, Chatrou ML, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RT, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res. 2015;116(8):1312-1323. https://doi.org/10.1161/CIRCRESAHA.116.305012.Kapustin AN, Chatrou ML, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RT, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res. 2015;116(8):1312-1323. https://doi.org/10.1161/CIRCRESAHA.116.305012.New SE, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K, Libby P, Shanahan CM, Croce K, Aikawa E. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 2013;113(1):72-77. https://doi.org/10.1161/CIRCRESAHA.113.301036.New SE, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K, Libby P, Shanahan CM, Croce K, Aikawa E. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 2013;113(1):72-77. https://doi.org/10.1161/CIRCRESAHA.113.301036.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.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.Cai MMX, Smith ER, Tan SJ, Hewitson TD, Holt SG. The Role of Secondary Calciprotein Particles in the Mineralisation Paradox of Chronic Kidney Disease. Calcif Tissue Int. 2017;101(6):570-580. https://doi.org/10.1007/s00223-017-0313-0.Cai MMX, Smith ER, Tan SJ, Hewitson TD, Holt SG. The Role of Secondary Calciprotein Particles in the Mineralisation Paradox of Chronic Kidney Disease. Calcif Tissue Int. 2017;101(6):570-580. https://doi.org/10.1007/s00223-017-0313-0.Blau R, Krivitsky A, Epshtein Y, Satchi-Fainaro R. Are nanoth-eranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine? Drug Resist Updat. 2016; 27: 39-58. https://doi.org/10.1016/j.drup.2016.06.003.Blau R, Krivitsky A, Epshtein Y, Satchi-Fainaro R. Are nanoth-eranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine? Drug Resist Updat. 2016; 27: 39-58. https://doi.org/10.1016/j.drup.2016.06.003.Matea WCT, Mocan T, Tabaran F, Pop T, Mosteanu O, Puia C, et al. Quantum dots in imaging, drug delivery and sensor applications. Int J Nanomedicine. 2017; 12: 5421-5431. https://doi.org/10.2147/IJN.S138624.Matea WCT, Mocan T, Tabaran F, Pop T, Mosteanu O, Puia C, et al. Quantum dots in imaging, drug delivery and sensor applications. Int J Nanomedicine. 2017; 12: 5421-5431. https://doi.org/10.2147/IJN.S138624.

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