{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T19:39:43Z","timestamp":1782589183498,"version":"3.54.5"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,4,10]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)\u2013driven arterial occlusion, tissue infarction, and organ failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>C57BL\/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain\u2013like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was &lt;3 hours after CC injection. However, combining Nec-1s (necrostatin-1s) prophylaxis given 1 hour before and DNase I 3 hours after CC injection completely prevented kidney failure and infarcts. In vitro, CC did not directly induce plasmatic coagulation but induced neutrophil extracellular trap formation and DNA release mainly from kidney endothelial cells, neutrophils, and few from platelets. CC induced ATP release from aggregating platelets, which increased fibrin formation in a DNase-dependent manner.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.315625","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T18:27:30Z","timestamp":1584556050000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism"],"prefix":"10.1161","volume":"126","author":[{"given":"Chongxu","family":"Shi","sequence":"first","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tehyung","family":"Kim","sequence":"additional","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Steiger","sequence":"additional","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrikant R.","family":"Mulay","sequence":"additional","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Klinkhammer","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Institute of Pathology (B.M.K, P.B.), RWTH Aachen University Hospital, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"B\u00e4uerle","sequence":"additional","affiliation":[{"name":"Preclinical Imaging Platform Erlangen, Institute of Radiology, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Germany (T.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Melica","sequence":"additional","affiliation":[{"name":"Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (M.E.M., P.R.), University of Florence, Italy"},{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d (M.E.M., P.R.), University of Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Romagnani","sequence":"additional","affiliation":[{"name":"Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (M.E.M., P.R.), University of Florence, Italy"},{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d (M.E.M., P.R.), University of Florence, Italy"},{"name":"Nephrology and Dialysis Unit, Meyer Children\u2019s University Hospital, Florence, Italy (P.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"M\u00f6ckel","sequence":"additional","affiliation":[{"name":"Institute for Experimental Molecular Imaging (D.M., M.B., T.L.), RWTH Aachen University Hospital, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Baues","sequence":"additional","affiliation":[{"name":"Institute for Experimental Molecular Imaging (D.M., M.B., T.L.), RWTH Aachen University Hospital, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luying","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne L.N.","family":"Brouns","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CARIM, Maastricht University, The Netherlands (S.L.N.B., J.W.M.H.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan W. M.","family":"Heemskerk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CARIM, Maastricht University, The Netherlands (S.L.N.B., J.W.M.H.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Braun","sequence":"additional","affiliation":[{"name":"Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, German Center for Lung Research, Germany (A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Twan","family":"Lammers","sequence":"additional","affiliation":[{"name":"Institute for Experimental Molecular Imaging (D.M., M.B., T.L.), RWTH Aachen University Hospital, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Boor","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Institute of Pathology (B.M.K, P.B.), RWTH Aachen University Hospital, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-2956","authenticated-orcid":false,"given":"Hans-Joachim","family":"Anders","sequence":"additional","affiliation":[{"name":"From the Medizinische Klinik und Poliklinik IV, Klinikum der Universit\u00e4t, LMU M\u00fcnchen, Germany (C.S., T.K., S.S., S.R.M., L.Y., H.-J.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32203-7"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2538"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2515"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1996.00440060081009"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/joic.12483"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199511000-00005"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)62073-0"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(99)70415-4"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.31.20160100"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2016.02.034"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.10"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.06.018"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000489940"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716959115"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716578115"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0394-3"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.205732"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1677040"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-018-0073-2"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.08.035"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24993"},{"key":"e_1_3_6_23_2","first-page":"203","article-title":"Neutrophil extracellular traps in tissue pathology.","volume":"32","author":"Nakazawa D","year":"2017","unstructured":"Nakazawa, D, Kumar, S, Desai, J, Anders, HJ. Neutrophil extracellular traps in tissue pathology. Histol Histopathol. 2017;32:203\u2013213. 10.14670\/HH-11-816","journal-title":"Histol Histopathol"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam8897"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2014.10.003"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-631259"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1601611"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0368-1319(64)80055-7"},{"key":"e_1_3_6_29_2","first-page":"469","article-title":"The ultrastructure of the stages of atheroembolic occlusion of renal arteries.","volume":"54","author":"Warren BA","year":"1973","unstructured":"Warren, BA, Vales, O. The ultrastructure of the stages of atheroembolic occlusion of renal arteries. Br J Exp Pathol. 1973;54:469\u2013478.","journal-title":"Br J Exp Pathol"},{"key":"e_1_3_6_30_2","first-page":"67","article-title":"The ultrastructure of the reaction of arterial walls to cholesterol crystals in atheroembolism.","volume":"57","author":"Warren BA","year":"1976","unstructured":"Warren, BA, Vales, O. The ultrastructure of the reaction of arterial walls to cholesterol crystals in atheroembolism. Br J Exp Pathol. 1976;57:67\u201377.","journal-title":"Br J Exp Pathol"},{"key":"e_1_3_6_31_2","first-page":"205","article-title":"Electron microscopy of the sequence of events in the atheroembolic occlusion of cerebral arteries in an animal model.","volume":"56","author":"Warren BA","year":"1975","unstructured":"Warren, BA, Vales, O. Electron microscopy of the sequence of events in the atheroembolic occlusion of cerebral arteries in an animal model. Br J Exp Pathol. 1975;56:205\u2013215.","journal-title":"Br J Exp Pathol"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12350-017-0826-y"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12447"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.450"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000263"},{"key":"e_1_3_6_36_2","first-page":"1437","article-title":"[Cholesterol crystal embolisms due to systemic thrombolysis of an acute myocardial infarct].","volume":"124","author":"Diethelm A","year":"1994","unstructured":"Diethelm, A, Vorburger, C, Anabitarte, M, Haag, E. [Cholesterol crystal embolisms due to systemic thrombolysis of an acute myocardial infarct]. Schweiz Med Wochenschr. 1994;124:1437\u20131441.","journal-title":"Schweiz Med Wochenschr"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1177\/1076029612440033"},{"key":"e_1_3_6_38_2","first-page":"317","article-title":"[Atheroembolic renal disease: analysis of clinical and therapeutic factors that influence its progression].","volume":"30","author":"Guti\u00e9rrez Sol\u00eds E","year":"2010","unstructured":"Guti\u00e9rrez Sol\u00eds, E, Morales, E, Rodr\u00edguez Jornet, A, Andreu, FJ, Rivera, F, Vozmediano, C, Guti\u00e9rrez, E, Igarz\u00e1bal, A, Enguita, AB, Praga, M. [Atheroembolic renal disease: analysis of clinical and therapeutic factors that influence its progression]. Nefrologia. 2010;30:317\u2013323. 10.3265\/Nefrologia.pre2010.Apr.10367","journal-title":"Nefrologia"},{"key":"e_1_3_6_39_2","first-page":"575","article-title":"[Multiple cholesterol emboli syndrome: beneficial effects of early heparin therapy. A case report].","volume":"48","author":"Lekeufack JB","year":"1999","unstructured":"Lekeufack, JB, Delr\u00e9e, P, Goergen, M, Bouazza, F, Salmon, K, Raynal, P, Azagra, JS, Sellitti, E, Dehon, P. [Multiple cholesterol emboli syndrome: beneficial effects of early heparin therapy. A case report]. Ann Cardiol Angeiol (Paris). 1999;48:575\u2013578.","journal-title":"Ann Cardiol Angeiol (Paris)"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2008.00425.x"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04544.x"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06893-7"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-573543"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao6047"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcin.2011.02.010"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780360118"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900503"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2018.05.068"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2014.06.006"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01163"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0149489"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00279.2012"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00619"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.07.024"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2008.12.028"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1515\/bchm2.1924.135.5-6.203"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.482"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015020204"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.13624"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1004542"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.119.315625","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T04:58:11Z","timestamp":1715576291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.119.315625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,10]]},"references-count":59,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,4,10]]}},"alternative-id":["10.1161\/CIRCRESAHA.119.315625"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.119.315625","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,10]]},"assertion":[{"value":"2019-06-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}